WO2023201442A1

WO2023201442A1 - Clonal haematopoiesis as a biomarker

Info

Publication number: WO2023201442A1
Application number: PCT/CA2023/050553
Authority: WO
Inventors: Filio BILLIA; Sagi ABELSON; John Dick; Robert VANNER
Original assignee: University Health Network
Current assignee: University Health Network
Priority date: 2022-04-22
Filing date: 2023-04-24
Publication date: 2023-10-26
Anticipated expiration: 2024-10-22
Also published as: US20250257408A1

Abstract

There is described herein methods predicting the risk of various disease condition by measuring clonal hematopoiesis in a patient, probes used to make such measurement and methods for treatment or preventive treatment of the disease condition.

Description

CLONAL HAEMATOPOIESIS AS A BIOMARKER

RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No. 63/333,628 filed on April 22, 2022, which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

The invention relates to the measurement of clonal haematopoiesis for the purposes of assessing the risk associated with various disease states, particularly relating to solid organs and/or cancer.

BACKGROUND OF THE INVENTION

Clonal haematopoiesis (CH) is the acquisition of mutations in hematopoietic stem cells that results in selective clonal expansion leading to enhanced systemic inflammation.⁵ While early studies had shown that at least 10% of individuals harbour CH mutations in their seventies,⁵ more sensitive techniques have demonstrated that CH mutations are ubiquitous in healthy middle-age adults.⁶⁷ Despite these mutations increasing the risk of haematological cancer development, progression to malignancy is low.⁸

Interestingly, CH is also associated with elevated cardiovascular risk;^{59 10} more than most traditional risk factors.¹¹ The presence of CH mutations is linked to a 25% increase in the incidence of de novo heart failure (HF) and a 2-fold increase in mortality in patients with pre-existing HF.^{9 12} In animal models of HF, mice harbouring CH mutations developed adverse left ventricular (LV) remodelling with fibrosis and a concomitant increase in IL-6 and IL-1 B.¹³

However, the incidence of CH in more specific cardiac diseases, specific cancers and diseases in other organs, and its impact in clinical outcomes, remains unknown. For example, cardiogenic shock (CS) is a life-threatening condition with markedly reduced cardiac output resulting in multi-organ failure.¹ Despite increasing recognition of CS and implementation of intensive therapies, morbidity and mortality remain exceedingly high.² The evolving epidemiological descriptions of CS patients illustrate that there is a large variability in the underlying aetiology, response to medical therapy, and outcomes.^{1 3} The association of a systemic inflammatory response syndrome with worse outcomes in CS³ could be a key to understanding the heterogeneity in the natural history of CS and uncover new pathways to target for treatment.⁴

Further, orthotopic heart transplant (OHT) is the treatment of choice for patients with advanced heart failure to improve quality of life and survival.⁵¹ In the United States, over 80,000 HT were performed in the past three decades and over 5,000 yearly worldwide.^{52 53} However, despite the improvement in donor and recipient pretransplant care, post-transplant survival is affected by a number of complications including infections due to long-term immunosuppression therapy, cancer development and cardiac allograft vasculopathy (CAV).⁵⁴- ⁵⁵ OHT recipients require extensive monitoring after transplantation with endomyocardial biopsies (EMB) for rejection vigilance, viral detection for opportunistic infection, echocardiograms and coronary angiography for allograft function and CAV assessment to instill early treatment and improve survival.⁴ Despite this intensive care, new non-invasive surveillance methods that could improve morbidity and reduce mortality are still warranted. ⁵⁶ The increased inflammatory cytokine/chemokine production linked to CH could also affect outcomes in OHT recipients, but this association has never been evaluated. ^{58 515}

There remains a need to study the link between CH and various disease states, including those listed above.

SUMMARY OF THE INVENTION

We hypothesized that the enhanced inflammatory environment associated with CH may play a significant role in various disease outcomes and its related complications. Therefore, we evaluated the prevalence of CH in patients with various cardiac diseases, solid organ diseases and specific cancers. In an aspect, there is provided a method of predicting the risk of a disease condition of a solid organ in a patient, the method comprising: receiving a sample from the patient containing hematopoietic stem cells; sequencing the sample to detect a degree of clonal hematopoiesis; comparing the degree of clonal hematopoiesis in the patient to a control degree; and determining the patient is at an elevated risk of the disease condition if the degree of clonal hematopoiesis in the patient is higher than the control degree in a statistically significant manner.

In an aspect, there is provided a kit comprising a library of probes library comprising at least 50%, 60%, 70%, 80%, 90%, 95%, 98% or 99% of the probes listed in Table A.

In an aspect, there is provided a method of predicting the benefit of immunotherapy in a patient with melanoma, the method comprising: receiving a sample from the patient containing hematopoietic stem cells; sequencing the sample to detect a degree of clonal hematopoiesis in TET2; comparing the degree of TET2 clonal hematopoiesis in the patient to a control degree; and determining the patient would benefit from immunotherapy if the degree of TET2 clonal hematopoiesis in the patient is higher than the control degree in a statistically significant manner. Preferably, the method further comprises treating the patient with immunotherapy.

In an aspect, there is provided a method of predicting metastatic risk in a patient with a non-hematological cancer, the method comprising: receiving a sample from the patient containing hematopoietic stem cells; sequencing the sample to detect a degree of clonal hematopoiesis in TET2; comparing the degree of TET2 clonal hematopoiesis in the patient to a control degree; and determining the patient is at a lower risk of metastasis if the degree of TET2 clonal hematopoiesis in the patient is higher than the control degree in a statistically significant manner. Preferably, the method further comprises treating the patient with a treatment and monitoring regimen reflective of a low risk of metastasis.

BRIEF DESCRIPTION OF FIGURES

These and other features of the preferred embodiments of the invention will become more apparent in the following detailed description in which reference is made to the appended drawings wherein: Figure 1. Study design. Cardiogenic shock patients were screened for eligibility and those with available biospecimen and consent were included. Ambulatory heart failure patients were screened on a digital database and those with complete data for age, sex, ejection fraction and aetiology of heart failure, available biospecimen and consent were included. Cardiogenic shock and ambulatory heart failure patients were matched on a 1 :1 ratio for age, sex, ejection fraction, and aetiology. Ambulatory heart failure and cardiogenic shock patients were sequenced for clonal haematopoiesis related genes and its prevalence was estimated. A survival analysis was performed in each group. A survival analysis for specific genes mutations and a cytokine profile were assessed in cardiogenic shock patients.

Figure 2. Somatic variant characteristics in cardiogenic shock cohorts and ambulatory heart failure. Panel A shows the number of mutations for the 10 most frequently mutated genes according to each cohort. Panel B shows the number of mutations per patient in those where a clonal haematopoiesis mutation was identified. Panel C shows the variant allele frequency boxplot for patients with a mutation with a VAF >2%. No differences were observed between cohorts (P=0.87). Panel D shows the number of patients with CH mutation according to age in both cohorts. Filled columns represent those with CH mutations, and unfilled those without.

Figure 3. Survival according to clonal haematopoiesis and specific gene mutations. Panels A, B and C shows the reduced survival in CS patients with CH mutations in 30- day, 90-day and 3-year survival respectively. Panels D, E and F shows the reduced survival in CS patients according to specific CH-related mutations (DNMT3A, ASLX1 and TET2) in 30-day, 90-day and 3-year survival respectively. All figures represents VAD/OHT censored survival analysis.

Figure 4. Inflammatory cytokines in CS patients with TET2 and ASXL1 mutations. Panel A shows the differences in SCD40L, IFNy, IL-4, TNF-a and abundance in plasma of patients with or without TET2 mutations of variant allele frequency >2%. Panel B shows the differences in CCL7 in patients with or without ASXL1 mutations with a variant allele frequency >2% (P=0.03).

Figure 5. Somatic clonal hematopoiesis gene mutations prevalence and characteristics in orthotopic heart transplant recipients. Panel A shows the frequency of CH in OHT recipients. Panel B shows the number of mutations according to genes related to CH. Panel C shows the number of patients with one, two, three, five and six CH mutations. Panel D shows the number of patients with CH mutations according to age. (CH, clonal hematopoiesis; OHT, orthotopic heart transplant).

Figure 6. Survival analysis in orthotopic heart transplant recipients according to the presence of clonal hematopoiesis gene mutations. (CH, clonal hematopoiesis)

Figure 7. Somatic mutations related to clonal hematopoiesis in patients with hypertrophic cardiomyopathy. Panel A shows the number of mutations in the most common affected genes in the cohort. Panel B shows the number of mutations per patients in those with clonal hematopoiesis. Panel C shows the number of patients with clonal hematopoiesis according to the decade of the assessment. (CH, clonal hematopoiesis; HCM, hypertrophic cardiomyopathy).

Figure 8. Survival in patients with hypertrophic cardiomyopathy stratified according to the presence of clonal hematopiesis. Panel A shows the survival according to the presence of clonal hematopoiesis among HCM patients. Panel B shows the survival according to the presence of clonal hematopiesis in the DNMT3A, TET2, and ASXL1 genes among HCM patients. Panel C shows the survival according to the presence of clonal hematopoiesis among HCM patients with sarcomeric mutations. Panel D shows the survival according to the presence of clonal hematopiesis in the DNMT3A, TET2, and ASXL1 genes among HCM patients with sarcomeric mutations. (CH, clonal hematopoiesis; HCM, hypertrophic cardiomyopathy).

Figure 9. Troponin I, cytokines and chemokines levels among HCM patients with sarcomeric mutations according to the presence of clonal hematopoiesis. (CH, clonal hematopoiesis; HCM, hypertrophic cardiomyopathy).

Figure 10. TET2-mutant clonal hematopoiesis is associated with clinical benefit from immunotherapy in melanoma. A) 569 patients with melanoma, bladder cancer, renal cell carcinoma (RCC), or non-small cell lung cancer (NSCLC) treated with immune- checkpoint blockade were screened for clonal hematopoiesis using publicly-available exome sequencing, with at least one mutation of variant allele frequency (VAF) >0.02 detected in 74 patients (datasets EGAD00001006632, SRP064805, SRP067938, SRP072934, SRP090294, SRP095809, SRP115658, SRP128156). B) TET2-mutant clonal hematopoiesis is associated with significantly higher odds of clinical benefit 6 months after receiving immunotherapy in melanoma patients (Odds Ratio = 5.98), but not bladder cancer, renal cell carcinoma, or non-small cell lung cancer patients (p value from Firth’s multivariate logistic regression adjusted for patient age, sex, study, and immune checkpoint). C) In an animal model of immunotherapy, mice with Tet2- mutant hematopoiesis - mimicking TET2-mutant clonal hematopoiesis - show enhanced response to PD-1 immune checkpoint blockade, while isotype control (ISO) treated tumours show identical growth kinetics (*p<0.05 by Mann-Whitney Test).

Figure 11. TET2-mutant clonal hematopoiesis is associated with lower risk of metastatic disease in patients with non-hematological cancers. A) 16,744 patients with metastatic or non-metastatic solid tumours from Nguyen et al. Cell, 2022 were tested for clonal hematopoiesis in Bolton et al. Nature Genetics, 2020 using the MSK- IMPACT targeted sequencing panel. CH mutations with variant allele frequency of at least 0.02 were detected in 19.5% of patients. B) The 5 most commonly detected clonal hematopoiesis mutations from A) are shown. C) Exposure to TET2-mutant CH is associated with lower risk of having metastatic cancer in patients from A) as assessed by multivariate logistic regression adjusted for age, sex, smoking status, and chemotherapy treatment. D) Exposure to TET2-CH is associated with significantly lower risk of having metastases in patients from A) with Non-Small Cell Lung and Breast Cancer, with a trend towards lower risk of metastases in colorectal and bladder cancer, as assessed by multivariate logistic regression adjusted for age, sex, smoking status, and chemotherapy treatment. Patients in A) with TET2-mutant CH have significantly few metastases detected on clinical imaging (E) and have fewer overall sites I organs involved with metastatic disease (F), p values from Wilcoxon Rank Sum Test.

Figure 12. Clonal hematopoiesis prevalence among the 782 transplant recipients.

Figure 13. Clonal hematopoiesis prevalence according to transplanted organ..

Figure 14. Clonal hematopoiesis mutated genes among the 782 transplant recipients.

Figure 15. Clonal hematopoiesis mutated genes among the 127 heart transplant recipients.

Figure 16. Clonal hematopoiesis mutated genes among the 90 lung transplant recipients.

Figure 17. Clonal hematopoiesis mutated genes among the 189 kidney transplant recipients. Figure 18. Clonal hematopoiesis mutated genes among the 374 liver transplant recipients.

Figure 19. Mortality according to the transplanted organ.

Figure 20. Mortality according to clonal hematopoiesis.

Figure 21. Mortality according to clonal hematopoiesis by transplanted recipients.

DETAILED DESCRIPTION

In the following description, numerous specific details are set forth to provide a thorough understanding of the invention. However, it is understood that the invention may be practiced without these specific details.

As noted above, we investigated the role that the enhanced inflammatory environment associated with CH may play in various disease outcomes and its related complications.

In one example, we studied cardiogenic shock (CS) and its association with variable systemic inflammation and whether it may be responsible for the patient heterogeneity and the exceedingly high mortality rate. Cardiovascular events have been associated with clonal haematopoiesis (CH) where specific gene mutations in hematopoietic stem cells lead to clonal expansion and the development of inflammation. This study aims to assess the prevalence of CH and its association with survival in a population of CS patients in a quaternary centre.

We compared the frequency of CH mutations among 341 CS patients and 345 ambulatory heart failure (HF) matched for age, sex, ejection fraction, and HF aetiology. The association of CH with survival and levels of circulating inflammatory cytokines was analysed. We detected 266 CH mutations in 149 of 686 (22%) patients. CS patients had a higher prevalence of CH-related mutations than HF patients (OR 1.5; 95% Cl 1.0-2.1 , P=0.02) and was associated with decreased survival (30-days: HR 2.7; 95% Cl 1.3-5.7, P=0.006; 90-days: HR 2.2; 95% Cl 1.3-3.9, P=0.003; and 3-years: HR 1.7; 95% Cl 1.1-2.8, P=0.01). TET2 or ASXL1 mutations were associated with lower survival in CS patients at all-time points (P<0.03). CS patients with TET2 mutations had higher circulating levels of SCD40L, IFNy, IL-4, and TNFa (P<0.04), while those with ASXL1 mutations had decreased levels of CCL7 (P=0.03).

CS patients have high frequency of CH, notably mutations in TET2 and ASXL1. This was associated with reduced survival and dysregulation of circulating inflammatory cytokines in those CS patients with CH.

Novel risk stratification and non-invasive surveillance methods are also needed in orthotopic heart transplant (OHT) to reduce morbidity and mortality post-transplant, and this was thus the focus of another example. The purpose of this study was to investigate the association between CH and OHT. Blood samples were collected from 127 OHT recipients. Error-corrected sequencing was used to detect CH-associated mutations. We evaluated the association between CH and acute cellular rejection, CMV infection, cardiac allograft vasculopathy (CAV), malignancies, and survival. CH mutations were detected in 26 (20.5%) patients, mostly in DNMT3A, ASXL1, and TET2. Patients with CH showed a higher frequency of CAV grade 2 or 3 (0% vs. 18%, P<0.001). Moreover, a higher mortality rate was observed in patients with CH [11 (42%) vs. 15 (15%), P=0.008] with an adjusted hazard ratio of 2.9 (95% Cl, 1.4-6.3; P=0.003). CH was not associated with acute cellular rejection, CMV infection or malignancies. The prevalence of CH in OHT recipients is higher than previously reported for the general population of the same age group, with an associated higher prevalence of CAV and mortality.

Similar studies were conducted with respect to hypertrophic cardiomyopathy, lung transplant, immunotherapy benefit in myleloma and metatstic risk of a non- hematological cancer.

Accordingly, in an aspect, there is provided a method of predicting the risk of a disease condition of a solid organ in a patient, the method comprising: receiving a sample from the patient containing hematopoietic stem cells; sequencing the sample to detect a degree of clonal hematopoiesis; comparing the degree of clonal hematopoiesis in the patient to a control degree; and determining the patient is at an elevated risk of the disease condition if the degree of clonal hematopoiesis in the patient is higher than the control degree in a statistically significant manner.

As used herein, the term “control” refers to a specific value or dataset that can be used as a reference to classify a measured value e.g. the wild type or frequency of mutations in a cohort. A person skilled in the art will appreciate that the comparison between the measurement in the test sample and the reference values in the control will depend on the control used.

As used herein “hematopoietic stem cell” refers to cells capable of developing into any blood cell, including mature myeloid and/or lymphoid cells. These cells are typically bone marrow, liver, spleen or cord blood in origin. Myeloid and lymphoid lineages both are involved in dendritic cell formation. Myeloid cells include monocytes, macrophages, neutrophils, basophils, eosinophils, erythrocytes, and megakaryocytes to platelets. Lymphoid cells include T cells, B cells, natural killer cells, and innate lymphoid cells.

The term “sample” as used herein refers to any fluid, cell or tissue sample from a subject that can be assayed for the mutations in hematopoietic stem cells described herein..

In some embodiments, the degree of clonal hematopoiesis is measured using a variant allele frequency of mutations determined to be associated with clonal hematopoiesis. Preferably, the variant allele frequency (VAF) is >2%. Further preferably, the VAF is > 5%.

In some embodiments, the following genes are sequenced in the sample: TET2, DNMT3A, and ASXL1 , and optionally one or more of, but preferably all of, BCOR, BRAF, CALR, CBL, CEBPA, EZH2, FLT3A, GATA1 , GATA2, GNAS, IDH1 , IDH2, JAK2, KIT, KRAS, MPL, NRAS, PHF6, PPM1 D, PTPN11 , RAD21 , RUNX1 , SETBP1 , SF3B1 , SMC1A, SMC3, SRSF2, STAG2, TP53, U2AF1 , WT1 , and ZRSR2.

In some embodiments, the sequencing is performed using single-molecule molecular inversion probes (smMIPs). The smMIPs technique is an assay that combines single molecule tagging with multiplex targeted capture to enable practical and highly sensitive detection of low-frequency or subclonal variation.

In some embodiments, the mutations associated with clonal hematopoiesis are detectable by the probes listed in Table A.

In some embodiments, the mutations associated with clonal hematopoiesis are detected using a library comprising at least 50%, 60%, 70%, 80%, 90%, 95%, 98% or

In some embodiments, the mutations associated with clonal hematopoiesis are detected using a library consisting of at least 50%, 60%, 70%, 80%, 90%, 95%, 98% or 99% of the probes listed in Table A.

In some embodiments, the mutations associated with clonal hematopoiesis are detected using a library consisting of substantially all of the probes listed in Table A.

In some embodiments, the mutations associated with clonal hematopoiesis are detected using a library consisting of the probes listed in Table A.

In some embodiments, the solid organ is a heart.

In some embodiments, the disease condition is cardiogenic shock. In some embodiments, an elevated risk of cardiogenic shock is associated with an elevated risk of death. Preferably, the method further comprises treating or preventatively treating the patient for cardiogenic shock.

In some embodiments, the disease condition is an adverse outcome after orthotopic heart transplant (OHT). In some embodiments, the adverse outcome is an elevated risk of mortality and/or elevated risk of cardiac allograft vasculopathy. Preferably, the method further comprises treating or preventatively treating the patient for cardiac allograft vasculopathy.

In some embodiments, the disease condition is hypertrophic cardiomyopathy. Preferably, the method further comprises treating or preventatively treating the patient for hypertrophic cardiomyopathy.

In some embodiments, the solid organ is a lung. In some embodiments, the disease condition is an adverse outcome, including death, after lung transplant. Preferably, the method further comprises treating or preventatively treating the patient for the adverse outcome after lung transplant.

In some embodiments, the kit comprises a library consisting of at least 50%, 60%, 70%, 80%, 90%, 95%, 98% or 99% of the probes listed in Table A. In some embodiments, the kit comprises a library consisting of substantially all of the probes listed in Table A.

In some embodiments, the kit comprises a library consisting of the probes listed in Table A.

The advantages of the present invention are further illustrated by the following examples. The examples and their particular details set forth herein are presented for illustration only and should not be construed as a limitation on the claims of the present invention. EXAMPLE 1

MATERIALS AND METHODS

Patient selection

We performed a retrospective study to evaluate the prevalence of CH in CS patients and compared it to matched stable ambulatory HF patients. Stable ambulatory HF patients were chosen as controls as there is a known relationship with CH. We screened 1 ,315 consecutive patient admission with CS admitted to the cardiac intensive care unit (CICU) at the Toronto General Hospital (Ontario, Canada) from January 2014 to December 2020, identifying 341 patients with suitable biospecimens and consent. CS was diagnosed based on international consensus.¹⁴ Only the first CICU admission was considered for inclusion into the study. We also screened 9,485 ambulatory HF patients with no previous history of CS, orthotopic heart transplant (OHT), durable ventricular assist device (VAD), or HF admission in the 12 months prior to biospecimen collection and clinical evaluation (N=583). We included all patients aged >18 years, with biospecimens stored in the Peter Munk Cardiac Centre Cardiovascular Biobank. We excluded patients with incomplete digital records, those who withdrew consent during follow-up, or low biospecimen quality (Figure 1).

Definition of clinical states of enrolled patients

Cardiogenic shock diagnosis was based on international consensus criteria¹⁴ which required a systolic blood pressure <90 mmHg for more than 30 minutes, or the need for inotrope/vasopressor support, signs of end-organ failure (clammy skin, capillary filling time >3 seconds, urine output <0.5 mL/kg/h, lactate level >4 mmol/L), or a low cardiac output <2.2 L/min/m² if receiving inotropes/vasopressors or <1.8 L/min/m² without inotropes/vasopressors). In contrast, we defined stable ambulatory HF as patients with HF, with no history of OHT or VAD, or HF admission in the 12 months up to the time-point of biospecimen collection.

Data collection

Clinical and laboratory data for CS patients were collected within the first 24 hours of CICU admission. The Society for Cardiovascular Angiography and Intervention (SCAI) CS stage¹⁴ was calculated at 24 hours after CICU admission. Data collected after this time were related to in-hospital outcomes such as use of mechanical circulatory support (MCS), renal replacement therapy, mechanical ventilation and death. Data for ambulatory HF patients were collected as close to the biospecimen collection date as possible. All study data were collected from electronic records and prior to CH sequencing.

Follow-up and Outcomes

All CS patients were followed until death or their last visit to our institution after hospital discharge. Follow-up time for the ambulatory HF group was defined from the time of biospecimen collection until the last visit to our institution or notice of death. As OHT and VAD substantially increase survival, a patient was right censored at the time of VAD, OHT or last follow-up, whichever was earlier. We reported event-free survival at 30-day, 90-day and 3-year. Similar to other studies,⁹ we defined CH-related mutations at a VAF cut-off >2%.

Biospecimens and analysis

Biospecimens were collected from patients during their admission to the CICU unit of the Toronto General Hospital with deferred consent. In the case that a patient, or their substitute decision-maker, denied consent at a later time point, the biospecimens were discarded. Biospecimens from ambulatory HF patients were obtained during routine heart function clinic visits at our institution. All samples were stored at -80°C at the Peter Munk Cardiac Centre biobank.

For patients with CS, biospecimens were collected within a median of 10 (interquartile range, IQR 67) days from CS admission. In the ambulatory HF patient group, 89% of biospecimens were collected on the same day as clinical evaluation. We felt the timing of biospecimen collection was appropriate as changes in clonal haematopoiesis do not occur over days, but rather over years.

Genetic Sequencing Procedures

Next-generation sequencing library construction was conducted with smMIPs.¹⁵

Cytokine Analysis

To define whether cytokine levels can be potential markers of inflammation, the analysis was restricted to those samples obtained during the admission to the CICU. Statistical analysis

All analyses on the frequency and associations with CH were performed with a variant allele frequency (VAF) cut-off >2%. For specific gene analysis, we compared patients with no mutation with those with a mutation in one of the three more common mutations (DNMT3A, TET2, or ASXL ) with a VAF >2% but with no overlap mutations. We also transformed VAF and cytokines levels using the logarithm function to reduce the distribution skewness.

A sample size of 345 patients for each group would detect a ratio of 1.5 in CH frequency between CS and ambulatory HF groups with a power of 87.5% and alpha of 0.05. There were 345 CS patients and 583 stable HF patients selected after initial screening. The CS and stable HF groups were one-to-one matched by age, sex, aetiology of HF, and ejection fraction. A nearest neighbour method was applied without replacement. After matching, there were 345 patients in each group. Figure 1 summarizes sample selection.

All variables were tested for normality with histogram analysis and Shapiro-Wilk test. Normal and non-normal continuous variables are presented as mean ± standard deviation or median (interquartile range), and categorical variables with frequencies. Between-cohort differences in continuous variables were evaluated with a Student’s t- test or Mann-Whitney accordingly. Between-cohort differences in categorical variables were evaluated with a chi-square test. Logistic regression was performed to quantify the association of the prevalence of CH between CS and ambulatory heart failure patients in terms of odds ratios. Next, we separately characterized the 30-day, 90-day and 3-year event-free survival for each cohort using the Kaplan-Meier survival method. Furthermore, within each cohort, we contrasted event-free survival in patients with and without CH in terms of hazard ratios (HR) using Cox proportional hazards regression and evaluated the survival differences using log-rank tests. The HRs in this descriptive analysis were not adjusted for covariates. Subsequently, we also quantified the association between CS and mortality both with age only and with other clinically relevant covariates (i.e., age, sex, aetiology, use of mechanical circulatory support, creatinine, sodium, and white blood count). The model was validated by the proportional hazard assumption test based on Schoenfeld residual. Finally, as a sensitivity analysis, we repeated the previous analyses on all-cause mortality without right censoring patients at the time of OHT and VAD implantation. We described and explored the event-free survival and the levels of 48 cytokines in patients with a single gene mutation in the three most commonly mutated genes to patients without any mutations. We used a statistical significance of 0.05 for all analyses and a two-sided p- value. All analyses were performed using SPSS, version 25.0 (SPSS Inc., NY, USA).

RESULTS AND DISCUSSION

In this study, 341 patients were included in the CS group and 345 in the ambulatory HF group. Four (1%) patients were excluded from the CS group due to poor biospecimen quality (Figure 1). All characteristics included in the case-control study were similar between groups (Table 1). Our study population consisted mostly of males with a predominance of non-ischemic cardiomyopathy. Patients with CS, however, had a lower body mass index, more frequent history of smoking, lower incidence of pre-existing chronic HF, higher admission serum creatinine and higher BNP when compared with ambulatory HF patients.

In the CS group, the most common aetiology was acute decompensation of chronic HF in 225 (66%) patients, followed by new onset HF in 93 (27%), myocardial infarction in 10 (3%) and myocarditis in 11 (3%). The majority were classified at SCAI stage D (285 patients, 83%) and pulmonary artery catheter was used in 178 (52%) patients confirming disease severity. Fifty-two (15%) patients required temporary MCS with intra-aortic balloon pump being the most commonly used (n=26, 8%), followed by extra-corporeal life support (n=18, 5%), and Impella device® (Abiomed Inc., Massachusetts, USA) (n=8, 2%). Mechanical ventilation was needed in 63 (18%) patients and renal replacement therapy in 35 (10%). Clinical characteristics are summarized for both CS patients (Table 2) and ambulatory HF (data not shown). CS patients were followed for a median of 676 (1289) days, while ambulatory HF patients were followed for 1246 (884) days.

In the CS group, 104 (30%) underwent OHT, 79 (23%) required durable VAD, 132 (39%) died during follow-up with 59 (17%) patients dying during the index hospitalization and 73 (21%) after hospital discharge. In the ambulatory HF group, 19 (6%) patients had OHT, seven (2%) were referred for durable VAD, and 35 (10%) patients died. Prevalence and distribution of CH mutations in the study groups

Overall, 422 mutations were identified in 28 genes, of which 266 (63%) mutations had a VAF > 2% and were included in the analysis (data not shown), affecting 149 (22%) of the 686 patients. The most common mutation type was missense, followed by frameshift, nonsense and splice site (data not shown). The most mutated gene was DNMT3A in 84 (32%), followed by TET2 in 48 (18%), and ASXL1 in 30 (11%) patients, with a similar distribution in mutations observed in both the CS and ambulatory HF groups (Figure 2A). Among all patients with CH, 83 (56%) had a single mutation, 35 (23%) had two and 31 (21%) had three or more (Figure 2B). The VAF distribution was similar in both populations (Figure 2C). As expected, an age-associated increase in CH prevalence (Figure 2D) was observed in both groups; however, the overall frequency of CH was significantly higher in CS patients, as compared with ambulatory HF patients (25.2% versus 18.3%; odds ratio, 1.5; 95% Cl 1.0-2.1 , P=0.02). CS patients with CH were older than those without mutations, and had a higher frequency of dyslipidaemia, lower sodium, and white blood count (Table 2). The frequency of CH in CS patients with previous HF was similar than those without out [24 (26%) vs. 24 (23%), P=0.54). Ambulatory HF patients with CH were older and more likely to have ischemic cardiomyopathy (data not shown).

Association between CH and survival

The presence of CH in the CS group was associated with an increased risk of death in a multivariable adjusted analysis for age, sex, aetiology of CS, use of mechanical circulatory support, creatinine, sodium, and white blood count and censored for VAD/OHT: 17 patients (20%) with CH died in the first 30-days compared with only 17 (7%) without mutations (hazard ratio, (HR), 2.7; 95% Cl 1.3 to 5.7, P=0.006; Figure 3A). A similar ratio was seen at 90-days (HR, 2.2; 95% Cl 1.3 to 3.9, P=0.003; Figure 3B). At 3 years, 36 patients (42%) with CH had died compared with 47 (18%) without detectable CH at initial admission for CS (HR, 1.7, 95% Cl 1.1 to 2.8, P=0.01 ; Figure 3C). Similar results were observed with the unadjusted and age-adjusted analysis for both uncensored and VAD/OHT censored (data not shown). There were no differences in survival between CH and non-CH groups in the ambulatory HF patients uncensored or VAD/OHT censored (data not shown). In addition, when considering VAF as a continuous variable, there was no association with death. However, analysis of VAF categorized as >2 to <5% and > 5% was associated with a higher risk of death in those with VAF > 5%, at 90-days and 3-years. Increasing number of mutated genes was not associated with death (data not shown).

We then stratified the CS group according to the three most mutated genes (DNMT3A, TET2, and ASXL1 , Figures 3D, 3E, 3F) and found an association for TET2 and ASXL1 mutations with decreased 30-day, 90-day, and 3-year survival compared with patients who had no CH mutations. Results for survival censored for VAD/OHT had similar results. DNMT3A mutations had no effect on survival at 30-day, 90-day or 3-year follow-up.

Cytokine expression in cardiogenic shock

To assess changes in the inflammatory milieu associated with CH, we compared 48 cytokines in the plasma of CS patients with mutations in the three most mutated genes, to those without CH. CS patients with TET2 mutations exhibited higher circulating levels of SCD40L, IFNy, IL-4, and TNFa (Figure 4A, 4B, 4C and 4D), and those with ASXL1 mutations had lower levels of CCL7 (Figure 4E) compared with patients lacking CH mutations. There were no differences in the cytokine profiles of patients with DNMT3A mutations (data not shown).

Discussion

CH mutations are associated with increased risk for adverse cardiovascular events in specific populations of patients with atherosclerosis and heart failure.^{59 10} We found that patients with CS had a 1.5-fold higher prevalence of CH as compared to ambulatory HF patients, with an associated decrease in 30-day, 90-day, and 3-year survival. The observed prevalence of CH in ambulatory HF patients (18.3%) is consistent with other reported findings, emphasizing the comparability of the methodology applied.^{9 16} Importantly, our data shows that CH may be considered as risk factor for CS admission regardless of prior HF. Of note, mutations specifically in TET2 and ASXL1 impacted the prognosis of CS and were associated with distinct circulating inflammatory cytokine profiles, compared with those patients without CH mutations. While the retrospective nature of this study may have introduced a survival bias, as CS patients who did not survive the first hours of presentation were less likely to have biospecimens taken, our study likely underestimates the prevalence of CH in CS. To our knowledge, this is the first study to show the higher prevalence of CH and lower survival in patients admitted with CS. DNMT3A was the most common mutated gene in both groups, followed by TET2 and ASXL1. These genes are epigenetic regulators with a role in altering DNA methylation to potentially promote stem cell self-renewal and clonal expansion.¹⁷ While DNMT3A is responsible for de novo DNA methylation, TET2 promotes demethylation.¹¹ ASXL1 has a role in chromatin regulation, promoting myeloid leukemogenesis.¹⁸ Although the mechanisms ascribed to these genes are still poorly understood, they likely boost systemic inflammation which may have an impact in CS.^{10 13 17} TET2 mutations were associated with a significant decrease in both short- and long-term survival in CS patients. These findings mirror previous work showing higher pathogenicity of mutations in TET2, compared to DNMT3A in the broader setting of HF.^{9 10 16 19} Additionally, ASXL1 mutations have been related to increased risk for myocardial infarction¹⁰ but its role in HF was unknown prior to our study. Here, we report a decrease of short- and long-term survival in ASXL1 carriers admitted with CS. DNMT3A mutations have been associated with HF hospitalization and death¹⁶, but this was not seen in our analysis. Mutations in DNMT3A may have lower pathogenicity in CS, explaining their higher frequency in this population.

CS is associated with acute systemic inflammation, which has been shown to increase mortality.⁴²⁰ Augmentation of this inflammatory state could explain the increased risk of death seen in CS patients with CH mutations. In our study, patients with CS harbouring TET2 mutations had elevated circulating levels of SCD40L, IFNy, IL-4, and TNF-a. SCD40L has a pro-inflammatory, pro-coagulant function associated with cardiovascular events related to atherosclerosis.^{21 22} IL-4 leads to tissue macrophage accumulation,²³ and increases IFNy expression, which has a key role in the adaptive immune response²⁴, and promotes myelopoiesis in response to inflammation²⁴²⁵. TNF- a is primarily produced by macrophages and can induce apoptosis in hematopoietic cells.²⁶²⁷ Additionally, ASXL1 mutations in CS patients were associated with lower circulating levels of CCL7, a chemokine that is a potent chemo-attractant for myeloid cells.²⁸ The differential regulation of cytokines promoted by specific CH mutation could enhance the immune response leading to reduced survival in TET2 and ASXL1 mutation carriers. The lack of any dysregulation of circulating cytokines with DNMT3A mutations offers an explanation why survival was not affected in our CS patients.

Clinically, the increasing incidence of CS remains a major limitation in patient management.² The association of CH mutations with higher mortality could provide a new biomarker to help identify patients at elevated risk, establishing a new paradigm of risk assessment in CS. The fact that CH patients were older does not explain the dramatic increase in mortality in CH patients, as the age-adjusted analysis showed similar results. Also, similar age differences between study populations were described in previous studies showing the impact of CH in cardiovascular outcomes.^{9 19} Mechanistically, the increased risk due to CH likely occurs through augmentation of the acute inflammatory state in CS. The altered cytokine profile may provide potential therapeutic targets in these patients. Prior studies have shown that decreased IL-6 receptor activity improved outcomes in patients with CH.²⁹ The development of smMIP-sq for CH assessment in our study should overcome the barrier to clinical implementation of other sequencing methods.^{16 19} Furthermore, the 2% VAF cut-off remains controversial. VAF reflects the size of the expanded clone evaluated in the peripheral blood and it is reasonable to hypothesize that risk increases with an increase in VAF.^{11 16 17} However, we did not find a difference in the VAF between CS patients and ambulatory HF, and its use as a continuous variable was not associated with increased mortality in CS patients. We did find that CH-associated risk increased with a categorized higher VAF cutoff.¹⁶ This may be explained by the highly-skewed distribution of VAF.

CS patients had a 50% higher prevalence of CH mutations than stable ambulatory HF patients. These mutations were associated with a 2-fold reduction in survival of CS patients. Specifically, mutations in TET2 and ASXL1 genes were shown to be more lethal than DNMT3A in this context and were associated with an altered profile of circulating inflammatory cytokines that may suggest a mechanism for CH to affect patient outcomes.

EXAMPLE 2

MATERIALS AND METHODS

Study population

We performed a retrospective study of 127 patients that underwent OHT in the Toronto General Hospital from 2005 to 2021. Only patients older than 18 with available biospecimens and complete clinical evaluation were included. No patients with active malignancies were included because it is considered a criteria for heart transplant candidacy.

Data collection

The clinical chart and pre-transplant assessment of OHT recipients were reviewed from the patients’ digital health records. We collected demographic data, medical history, laboratory assessment, date of OHT, transplant-related treatment at the time of the procedure and the immunosuppressive regimen at 1-yeart post-OHT, the occurrence and grade of acute cellular rejection episodes, CMV infection, CAV, any malignancy and death. All baseline characteristics regarding demographic and comorbidities were collected as close as possible to the biospecimens collection date because of its relationship with CH mutations.

Follow-up and outcomes

Patients were followed from the time of OHT procedure to the last visit at our institution or death. The patients were evaluated for the following outcomes: the first occurrence of acute cellular rejection, CMV infection, de novo post-transplant malignancy, CAV, and death.

Cellular rejection episode was diagnosed and classified according to the International Society for Heart and Lung Transplantation (ISHLT). ^s4 A positive cellular rejection episode was defined as the occurrence of 2R and 3R classification in EMB performed routinely or due to clinical suspicion of cellular rejection. As a routine, patients are routinely evaluated for rejection in weeks 1-4, 6, 8, 10 and months 3-6, 9, 12, 18, 24. Gene-expression profiling was also used for rejection surveillance in low-risk patients at our center, with a gene-expression derived high-risk score verified by confirmatory EMB. CMV assessment was performed when infection was suspected or when prophylaxis was discontinued. CMV infection was defined as positive PCR in peripheral blood regardless of clinical symptoms. Post-OHT malignancy vigilance is performed routinely by our centre and the diagnosis is based on tissue biopsy showing malignant neoplastic cells. OHT recipients have coronary angiography performed with intravascular ultrasound at 3 months, 12 months, 1-year and 5-years post OHT, though this may be deferred if intercurrent illness or significant kidney disease is present. The findings are graded according to the ISHLT criteria for CAV and considered positive in the presence of CAV2 or CAV3. ^s4 In the survival analysis, we considered death from any cause in the end of follow-up.

Genetic Sequencing Procedures

Peripheral blood samples were collected with patient consent during clinical visits to Toronto General Hospital and were stored in the Peter Munk Cardiac Centre biobank. 100ng of DNA was used to construct sequencing libraries using single molecule Molecular Inversion Probes (smMIP) as previously described. ^s16 Paired-end 150bp sequencing reads were generated using the Illumina Novaseq platform (Illumina Inc., California, USA).

Statistical analysis

All variables were tested for normality using the Shapiro-Wilk test. Normal and nonnormal continuous variables are presented as mean ± standard deviation or median (interquartile range). Difference among groups were evaluated with a Student’s t-test or Mann-Whitney accordingly. Group differences in categorical variables were evaluated with a chi-square test or Fisher’s exact test as appropriate. The hazard ratios (HR) for the event-free survival for OHT patients with or without CH was calculated using the Cox proportional hazards regression. An adjusted Cox proportional hazards regression including age, sex, primary heart failure diagnosis (ischemic, non-ischemic and congenital) and chronic kidney disease was also calculated to estimate the impact of CH on survival. The model was ascertained by the proportional hazard assumption test based on Schoenfeld residual and found to be valid. The survival function is represented graphically using Kaplan-Meier curves and compared according to the presence of CH mutations using log-rank test. We used a statistical significance of 0.05 for all analyses and a two-sided p-value. All analyses were performed using SPSS, version 25.0 (SPSS Inc., NY, USA).

RESULTS AND DISCUSSION

Study participants

Between 2005 and 2021 , 589 patients underwent OHT at our institution. 127 patients (21.5%) were included in this study. 97 males and 30 females. Their mean age was 49±14 years. The most common comorbidities were prior smoking (n=34, 27%), hypertension (n=33, 26%), dyslipidemia (n=33, 26%) and type 2 diabetes (n=28, 22%). 90 patients (71%) were diagnosed with underlying non-ischemic HF prior to OHT while 28 patients (22%) had ischemic heart disease. Transplantation was conducted in 44 (35%) patients with a ventricular assist devices (VAD). All patients received induction therapy, with the vast majority (n-123, 97%) receiving rabbit anti-thymocyte globulin. The most common immunosuppressive therapy regimen at hospital discharge included tacrolimus (n=119, 94%), sodium mycophenolate (n=123, 97%) and corticosteroids (n=127, 100%). Table 3 summarizes the patient’s baseline characteristics.

Evaluation of CH in OHT recipients

The targeted sequencing of CH genes was successfully performed in all patients. In 87 (68%) cases, samples were collected before the procedure with a median time from sample to procedure of 200 (IQR 428) days, and in 40 (32%) cases the sample was collected after the transplant, with a median time from the procedure to the sample collection of 114 (IQR 624) days. We observed 46 CH mutations in 26 (20%) OHT recipients (Figure 1A) with a median variant allele frequency (VAF) of 8.6% (3.2-35.9). The most commonly affected genes were DNMT3A in 11 (9%), ASXL1 in 5 (4%), and TET2 in 4 (3%). TP53, PPM1D, and CEBPA affected two (2%) patients each, while JAK2, IDH2, SF3B1 and SMC1A were found in one (1%) patient each (Figure 2B). Most patients (N=16, 62%) with CH had only one mutation (Figure 3C). Clinical characteristics of patients with specific CH mutations were summarized (data not shown). The list of variants detected can be found in Table 5. Gene mutations and the VAF according to immunosuppressive regimen at hospital discharge were summarized (data not shown).

OHT patients with CH were older than those without mutation (54±13 vs 48±14 years, P=0.04) and were followed for a longer period after OHT (4.3±3.9 vs. 2.9±2.1 , P=0.01). CH carriers also received an organ from EBV+ donor less frequently than those without CH [16 (62%) vs. 81 (80%), P=0.02], At hospital discharge, CH patients were less likely to receive tacrolimus [22 (85%) vs. 97 (96%) P=0.03], and sodium mycophenolate [23 (89%) vs. 100 (99%), P=0.006], There were no statistically significant differences in the prevalence of cardiovascular risk factors (diabetes, hypertension, BMI, smoking, dyslipidemia) or pre-OHT HF etiology between patients with and without CH (Table 3). CH is associated with increase mortality in the setting of OHT

The mean follow-up post-OHT was 3.2±2.6 years. Primary graft dysfunction occurred in 19 (15%) with an in-hospital mortality post-OHT of 9%. During follow-up, 59 (46%) patients had CMV infection, 69 (54%) had at least one 2/3R acute cellular rejection episode, 11 (9%) had post-transplant malignancy, 4 (3%) CAV grade 2 or 3, and 26 (20%) died.

All four CAV diagnosis occurred OHT recipients with CH (18%; P<0.001), but no CAV was found among those without CH. The number of patients assessed for CAV with coronary angiogram was similar between patients with CH and those without CH CH [17 (65%). Vs. 68 (67%), P=0.85], and also time from OHT to first coronary angiogram 441 (1192) days vs. 399 (107) days, P=0.19. Patients with CH showed a higher mortality rate than those without CH [11 (42%) vs. 15 (15%), P=0.008], with an unadjusted hazard ratio (HR) of 3.1 (95% Cl 1.4-6.7), P=0.005, and an adjusted HR of 2.9 (95% Cl 1.4-6.3; P=0.003). The clinical characteristics and cause of death of patients with our without CH were summarized (data not shown). Because CH patients had a trend towards more Cyclosporine prescription at discharge and at the end of the first year after OHT, we performed an sensitivity analysis with age and type of immunosuppressive drugs in the of the 1^st year. The adjusted model showed that CH was associated with increased mortality with an HR of 5.9 (95% Cl 1.7-19.9), P=0.004. Figure 2 shows the Kaplan-Meier survival analysis with an increased mortality in those with CH (P log-rank =0.003). The evaluation of outcomes according to specific gene mutation showed that more acute cellular rejection 2/3R were observed in those with DNMT3A, more CAV grade 2/3 in patients with DNMT3A and with TET2, and higher mortality in those with TET2 gene mutation (data not shown). We did not observe a higher mortality in patients with a VAF>10% (n=14) in comparison to those with VAF<10% (N=113) [5 (35.7%) vs. 21 (18.6%), P=0.31j. Considering our results, we undertook a post-hoc power calculation. With a sample size of 127 patients and a hazard ratio of 3.1 for OHT survival, given an alpha of 0.05, we would have a power of 99.2% of detecting such a difference. No differences were observed between OHT patients with or without CH regarding CMV infection, 2/3R acute cellular rejection or post-transplant malignancy. Both cases of post-OHT malignancy in patients with CH were diagnosed with squamous cell carcinoma of the skin, and one also developed lung carcinoma. No patients developed PTLD. Table 4 summarizes outcomes in OHT recipients according to CH. Discussion

CH has been linked to inflammatory conditions, increased mortality and incidence of cardiovascular diseases, but data in the setting of solid organ transplantation is scarce. s8, si7 _We showed that the CH prevalence in OHT recipients is higher than expected for the same age in the general population. CH mutations are associated CAV and a 3- fold increase in mortality after OHT. These findings suggests a new biomarker in posttransplantation risk assessment.

The detection of CH is an exceedingly common feature of aging, with a prevalence of 10% by the 7^th decade of life and an overall prevalence of 4-5%. ^s7 In this study, 20% of OHT recipients were found to have a CH mutation in a younger population, mainly in DNMT3A, ASXL1 and TET2 genes, with most patients harboring a single mutation. Previously, HF patients were shown to have an 18.5% frequency in CH mutations at a median age of 65 years. ^s1° ^s14 Similarly, the median VAF in our cohort was 12%, which is much higher than the reported =4-6% in non-advanced HF cohorts. ^s1° ^s14 Additionally, CH patients have been consistently reported to be older than those without these mutation, similar to our study. While concerns can been raised about CH being a risk marker of aging instead of a disease-driving factor, several studies have shown that CH is independently associated with increased cardiovascular risk after adjusting for age. ^s1° ^s14 CH has also been shown to have a causal effect in mice harboring either Dnmt3a, Tet2, Jak2, Tp53, and Ppmld mutations with adverse LV remodeling, lower LV ejection fraction and worsening degree of fibrosis post- myocardial infarction. ^{s151 s18}-^s21

CH mutations have been shown to be associated with atherosclerosis, myocardial infarction, stroke and HF. ^s8-^s1° ^s14 A similar background of inflammation driving clinical outcomes would be expected in OHT recipients. In our study, CH was associated CAV grade 3. Experimental models have shown that 7ef2-deficient mice have larger atherosclerotic plaque size and increased levels of several inflammatory cytokines. ^s8 ^s22 Higher levels of coronary artery disease have been observed in patients with CH. ^s8 The pathways involved in atherosclerosis development overlap with the inflammatory background of CH, but the pathophysiology of CAV comprises a complex interaction of immune and non-immune factors which contribute to a pro-inflammatory state and ultimately result in endothelial injury, vascular cell proliferation, fibrosis, and remodeling. ^s28“ ^s25 The increased inflammatory cytokines expressed in patients with CH could have a role in CAV development, but further studies are needed to confirm this hypothesis, especially due to the low number of CAV diagnosis in the sample.

The complex relationship of immune phenomena and inflammation promoted by CH could be responsible for other outcomes in OHT recipients. The innate immune system can be activated by several different cytokines resulting in rejection episode ^{s26 s27}, and activation of IL-1 R pathway has a central role in ischemic reperfusion injury. ^s28 However, despite the overall higher proportion of CH patients experiencing acute cellular rejection, it failed to reach statistical significance. One possibility is that based on the 16% absolute increase observed, a sample size of over 400 patients would be required to reach statistical significance. CH has also been associated with the occurrence of infections and malignancies. ^{s11 s12} We observed only a small number of such events which may explain the lack of association of CH with these outcomes. Nevertheless, CH was associated with a 3-fold increase in mortality in OHT recipients even after adjustment for confounding factors. Cardiovascular events in CH patients have been shown to be related with ischemic events and progression to heart failure, but these are not common in OHT recipients. ^{s8 s1}° ^s14 The cause of death in this study was related to allograft dysfunction, acute rejection episode, CAV, and septic shock. The mechanisms responsible for the observed high mortality rate remains unclear, yet previous work have shown that non-survivors after OHT were more likely to present with sustained inflammation. ^s29 Nonetheless, patients with CH were older, and, despite not being statistically significant, also had higher frequency of hypertension, dyslipidemia and smoking that could have an impact in our results.

In summary, we demonstrated that CH is associated with, and a potential risk factor, for CAV and mortality in OHT recipients. The complex interaction of the inflammatory cytokines promoted by CH and the immune system could drive several other potential outcomes such as rejection, infections and malignancies. A prior case series of graft versus host disease in transplanted liver patients showed that 71% had CH, highlighting the possible association with these somatic mutations to adverse outcomes. ^s8° EXAMPLE 3

METHODS AND MATERIALS

We investigated a cohort of patients with hypertrophic cardiomyopathy (HCM) submitted to targeted sequencing for detecting CH. We included 799 patients who were > 18 years of age, with a clinical diagnosis of HCM by current guidelines²², cardiac magnetic resonance imaging (MRI) and available biospecimens from the PMCC Biobank. We excluded patients with incomplete records, those that withdraw consent, or low biospecimen quality.

Among the 799 included patients, CH was found in 183 (22.9%). HCM patients with genotype-positive and CH were found to be more symptomatic and with a higher burden of fibrosis. CH was associated with major cardiovascular event (MACE) in HCM patients [adjusted HR of 3.46 (95% Cl 1.25-9.52; p=0.016)], with the highest risk among genotype-positive and DNMT3A, TET2 and ASXL1 mutated genes [adjusted HR of 7.23 (95% Cl 1.79-29.13) p=0.005]. Several cytokine and chemokines (IL-1 ra, IL-6, IL-17F, TGFa, CCL21 , CCL1 , CCL8, and CCL17), and also troponin I were upregulated in those genotype-positive with CH. Fibrosis, a hallmark of HCM, was found to be increased in those with CH, as well as ABPR at exercise. CH was also associated with a higher mortality and major cardiovascular events (MACE). These results indicate that CH is frequent among HCM patients and associated with a worse clinical phenotype and outcomes.

Definitions

HCM was defined as the presence of maximal LV wall thickness (MLVWT) > 15 mm. Also included were patients with MLVWT > 13 mm and a P/LP genetic variant or a family history of HCM in the absence of other causes for hypertrophy. MLVWT was defined as the higher LV wall measure on echocardiogram or cardiac MRI. The assessment of P/LP variants was conducted using a previously published strategy by our group²³. Evaluation for non-sustained ventricular tachycardia (NSVT) or abnormal blood pressure response (ABPR) at exercise were performed according to the attending clinician discretion. All patients with HCM underwent cardiac MRI with late gadolinium enhancement (LGE) for quantification of fibrosis. The LGE was assessed visually and quantified manually as previously validated⁸. LGE extent was defined as the LGE mass percentage of the total LV mass. We were able to quantify LGE in (84.1%) of patients with MRI. In the remaining 127 (15.9%) patients, we only included the qualitative measure of LGE as present or not.

Clonal hematopoiesis and cytokine assessment

The full method on CH and cytokines evaluation was performed substantially as described in earlier examples. Briefly, we used a single molecule molecular inversion probe (smMIP) method including 35 myeloid genes related to CH and smMIP-tools to call mutations and reported those with variant allele frequency (VAF), a measure of clone size, >2% for all analysis. The cytokine analysis was performed using a human cytokine/chemokine 71-plex assay with the Luminex™ 200 system by Eve Technologies Corp. (Alberta, Canada) and included brain natriuretic peptide (BNP) and cardiac troponin I (cTnl).

RESULTS AND DISCUSSION

Clonal hematopoiesis prevalence and characteristics

Overall characteristic of cohort is summarized in Table 7. The median time from biospecimen collection to the echocardiogram was 0 (0-16) days and median time from biospecimen to MRI assessment was 2.2 (0.2-5.6) years.

All patients had an assessment of CH performed and all samples passed quality control specifications. CH mutations were observed in 183 (22.9%) patients with a median VAF of 6.7 (2.8-40.8)%, being 136 (17.0%) in the three most common genes: DNMT3A in 70 (8.8%), TET2 in 51 (6.3%), and ASXL1 in 24 (3.0%), comprising 73.8% of all CH mutations. All other genes included in the smMIP panel were present in less than 1% of patients. Most patients (158, 19.8%) harbored a single mutation, while two mutations were found in 18 (2.3%) patients, 4 (0.5%) three mutations, and 3 (0.3%) four or more mutations. Among the 183 patients with CH, 135 (73.7%) were over 50 years old. However, among the 54 patients <30 years, CH was present in 14 (25.9%). In relation to the age of HCM diagnosis, 27 (14.8%) patients with CH were diagnosis before 30 years of age, while 62 (33.8%) within 31-50 years, and the majority, 94 (51.3%), were diagnosed after 50 years old. Figure 7 summarizes CH mutations characteristics. Overall clinical characteristics of CH patients were similar to those without CH (Table 7). We then analyzed the association of CH with the HCM phenotype. No differences were found in those with or without CH on echocardiographic parameter such as MLVWT (18.3±4.2 mm vs. 18.8±5.1 mm, p=0.256), left atrium diameter (36.7±14.5 mm vs. 38.1 ±12.7 mm, p=0.208) and LVOT gradient (24.1 ±36.2 mmHg vs. 22.1 ±34.6 mmHg, p=0.491). Cardiac MRI parameters, including the presence of fibrosis evaluated by LGE, as well as other HCM features such as syncope, ABPR at exercise, among others were also similar between groups. However, apical aneurysm [33 (5.4%) vs. 14 (7.7)%, p=0.004] and death or need for orthotopic heart transplant was higher among patients with CH [4 (0.6%) vs. 6 (3.3%), p=0.005], MACE was also more frequent among patients with CH [12 (2.0%) vs. 9 (5.2%), p=0.026], with an unadjusted HR of 2.72 (95% Cl 1.14-6.49; p=0.023), and adjusted HR of 3.46 (95% Cl 1.25-9.52; p=0.016). CH patients showed a worse survival in comparison to those without CH as shown in the Kaplan-Meier curve (Log-Rank P=0.018) (Figure 8A).

Clonal hematopoiesis related to DNMT3A, TET2 and ASXL1

We evaluated whether somatic mutations in 3 genes (DNMT3A, TET2 and ASXL1) alone are sufficient to drive poor HCM patient outcome. We found that patients harboring DNMT3A, TET2 and ASXL1 mutations were older than their counterparts [55.3 (14.5%) vs. 58.1 (14.5%), p=0.042] and were more likely to have a family history of SCD [28 (4.2%) vs. 9 (6.7%), p=0.038]. As we noted in the wider CH analysis, these patients were more likely to have hypertension, a P/LP germline HCM related mutation, a pacemaker and treated with a non-dihydropyridine calcium channel blocker (Table 6).

While patients with DNMT3A, TET2 and ASXL1 CH mutations, exhibited a similar HCM phenotype to those without CH, patients with CH showed a higher mortality or need for orthotopic heart transplant [4 (0.6%) vs. 6 (4.4%), p<0.0001] and MACE [13 (2.0%) vs. 8 (6.2%), p=0.008]. The unadjusted HR for MACE was 3.19 (95% Cl 1.32- 7.73; p=0.010) and adjusted HR 3.97 (95% Cl 1.39-11.28; p=0.010). Figure 8B shows the Kaplan-Meir curve with worse survival for patients with CH (Log-Rank p=0.006).

Clonal hematopoiesis in HCM patients with a sarcomeric mutation

HCM patients harboring a sarcomeric gene mutation are associated with early age at diagnosis, higher MLVWT and worse outcomes²⁵ . Because this subtype of HCM patients have a distinct clinical profile, we sought to investigate if there could be a distinct interaction with CH. The overall characteristics shown among those with or without CH were recorded (data not shown). A trend of a higher burden of symptoms (NYHA class II to IV) [15 (40.5%) versus 47 (28.0%), p=0.132] among those with CH, but it was not statistically significant. However, CH was associated with a higher burden of fibrosis as reflected by LGE in >15% of the LV mass [11 (29.7%) versus 26 (15.3%), p=0.044], with an odds ratio of 2.32 (95% Cl 1.00-5.38, p=0.048), there was a trend towards a higher amount of fibrosis in the LV of those with CH [15.6 % (10.4- 24.6)] in comparison to those without CH [12.2 % (7.7-17.6)], p=0.068. CH patients also showed a higher frequency of ABPR at exercise [25 (29.8%) vs. 10 (62.5%), p=0.012]. Finally, CH was associated with worse outcomes with higher mortality or orthotopic heart transplant [3 (8.1%) versus 2 (1.2%), (p=0.013)]. This was also observed for MACE in patients with CH [ 5 (13.5%) versus 5 (3.0%), p=0.008], with an unadjusted HR of 5.28 (95% Cl 1.51-18.4, p=0.009), and adjusted HR of 6.89 (95% Cl 1.78-26.6, p=0.005). Figure 8C shows the Kaplan-Meier survival curve showing a worse survival for those with CH (log-rank p=0.003).

We then stratified the HCM phenotype and clinical outcomes in those with sarcomeric mutations and specifically the presence of DNMT3A, TET2, and ASXL1 mutations. Baseline characteristics was similar between groups. The amount of fibrosis assessed by LGE was higher in those with CH [21.2% (13.7-41.8) versus 12.2% (7.7-17.5), p=0.014], whereas LGE >15% was not statistically different in HCM patients with and without CH [7 (35.0%) vs. 30 (18.3%), p=0.09]. However, CH patients showed a higher frequency of abnormal blood pressure response (ABPR) with exercise than those without CH [8 (66.7%) vs. 27 (30.7%), p=0.014). Finally, mortality or orthotopic heart transplant was more common in the CH group than in those without CH [3 (13.0%) vs. 2 (1.1%), p<0.0001], as well as MACE [4 (17.4%) vs. 6 (3.2%), p=0.004], MACE was associated with CH with an unadjusted HR of 5.04 (95%CI 1.39-18.28) p=0.014 and adjusted HR of 7.23 (95% Cl 1.79-29.13) p=0.005. Figure 8D shows the Kaplan-Meier survival curve showing a worse survival for those with CH (log-rank p=0.007).

Biomarkers and cytokines/chemokines

A panel of 71 cytokines and chemokines, BNP and cardiac troponin I were evaluated in patients with a sarcomeric mutation and levels were compared among those with (N=37) or without CH (N=169). It was observed that troponin I (p=0.008), IL-1 ra (p=0.037), IL-6 (p=0.028), IL-17F (p=0.006), TGFa (p=0.005), CCL21 (p=0.036), CCL1 (p=0.002), CCL8 (p=0.036), and CCL17 (p=0.047) were all upregulated in patients with CH. Figure 9 shows levels measured among those with and without CH. We then sought to investigate if specific CH mutations were associated with specific cytokines/chemokines. In HCM patients with sarcomeric mutations, those with CH due to DNMT3A (N=16) mutations showed higher levels of IL-9 (p=0.03 (p=0.046). TET2 CH carriers (N=6) showed higher levels of troponin (p=0.012), IL-10 (p=0.010), CXCL10 (p=0.001), CXCL9 (p=0.012), C VEFG-A (p=0.041), CCL21 (p=0.013), CXCL13 (BCAp=0.012) and

Finally, CH due to ASXL1 (N=2) did not show any differences in comparison to those without CH..

Discussion

In this study, we showed that CH prevalence among HCM patients is higher than described in the general population. Fibrosis, a known SCD risk factor, was more prevalent among CH patients with HCM sarcomeric gene mutations. We also observed higher burden of symptoms and higher frequency of ABPR during exercise among CH patients. Finally, CH was associated with higher mortality or orthotopic heart transplant and MACE. Several cytokines, chemokines and troponin were differently expressed in HCM patients with CH, highlighting a plausible causal relationship with the phenotype and outcomes. This is the first cohort in which there is an association between CH prevalence, HCM phenotype and clinical outcomes.

To our knowledge, this is the first study to evaluate the prevalence of CH in patients with HCM. In this study, we found that 22.9% of HCM patients harbored CH.

When restricting analysis to the three specific genes DNMT3A, TET2 and ASXL1 , we observed that 17% of HCM patients harbored CH mutations.

Fibrosis was more common in those patients with HCM who have a sarcomeric mutation and specific DNMT3A, TET2 and ASXL1 mutations. This is an important finding as fibrosis is linked to SCD in patients with HCM⁴⁰. In addition, ABPR at exercise, a known marker of SCD risk and worse outcomes⁴¹"¹³, was also more frequent among those with CH and HCM with sarcomeric mutations. This result potentially illustrates that CH could affect the HCM phenotype and promote adverse outcomes in patients with HCM. We showed that, in subsets of HCM patients and evaluating for overall CH or specific CH mutations, the mortality or need for orthotopic heart transplant is increased among CH patients even when adjusting for confounding factors. Moreover, condensing important major cardiovascular events in HCM, such as stroke, sudden cardiac death, appropriate ICD shock, death or orthotopic heart transplant, CH increases its risk in all subsets of patients, reaching the highest risk among those with sarcomeric mutations and with specific CH genes. Our results show that CH is a new risk factor among HCM patients. In fact, HCM patients with sarcomeric mutations with CH on the most common genes showed the worse survival (17%), contrasting to recent cohorts showing that HCM patients have a low mortality.⁹ Our results do not show a clear evidence of which mechanisms CH increase mortality in HCM, but its strong association with ageing¹³ leads us to hypothesize that the epigenic ageing and the inflammatory milieu may have a causal relationship with the reduced survival.

Among HCM with sarcomeric mutations, CH was associated with several inflammatory cytokines and chemokines such as IL-1 ra, IL-6, IL-17F, TGFa, CCL21 , CCL1 , CCL8, and CCL17, but also with troponin I, a marker of myocyte injury that is associates with clinical outcomes in HCM.⁴⁷ However, specific CH mutations may have distinct prognosis and inflammatory profiles.¹⁴³⁴ We observed that DNMT3A driven CH was associated with IL-9 and CXCL12. TET2 driven CH was associated with the higher number of differently expressed cytokines/chemokines including troponin I among all tested genes. DNMT3A was associated with LV remodeling and worse outcomes, but the high frequency CH mediated by this gene in the population could be explained by its low lethality and lower burden of inflammation, introducing a survival bias.^{11 19282934} Cardiac aging processes mediated by TET2 have shown to produce an enhanced inflammatory background that could be related to hypertrophy and fibrosis, but the worse prognosis associated with TET2 could also explain its lower frequency in studies.^{11 1729} ASXL1 carriers did not show different levels of expressed cytokines, chemokines, BNP or Troponin I. We believe that the low number of patients with this specific mutation could explain the results.

EXAMPLE 4

We also investigated TET2 mutant clonal hematopoiesis and its association with the benefit of immunotherapy, as well as metastasis of non-hematological cancers. Referring to Figure 10, TET2-mutant clonal hematopoiesis is associated with clinical benefit from immunotherapy in melanoma. Figure 10A shows 569 patients with melanoma, bladder cancer, renal cell carcinoma (RCC), or non-small cell lung cancer (NSCLC) treated with immune-checkpoint blockade were screened for clonal hematopoiesis using publicly-available exome sequencing, with at least one mutation of variant allele frequency (VAF) >0.02 detected in 74 patients (datasets EGAD00001006632, SRP064805, SRP067938, SRP072934, SRP090294, SRP095809, SRP115658, SRP128156). Figure 10B shows TET2-mutant clonal hematopoiesis is associated with significantly higher odds of clinical benefit 6 months after receiving immunotherapy in melanoma patients (Odds Ratio = 5.98), but not bladder cancer, renal cell carcinoma, or non-small cell lung cancer patients (p value from Firth’s multivariate logistic regression adjusted for patient age, sex, study, and immune checkpoint). Figure 10C shows in an animal model of immunotherapy, mice with Tet2-mutant hematopoiesis - mimicking TET2-mutant clonal hematopoiesis - show enhanced response to PD-1 immune checkpoint blockade, while isotype control (ISO) treated tumours show identical growth kinetics (*p<0.05 by Mann- Whitney Test).

Referring to Figure 11 , TET2-mutant clonal hematopoiesis is associated with lower risk of metastatic disease in patients with non-hematological cancers. Figure 11A shows 16,744 patients with metastatic or non-metastatic solid tumours from Nguyen et al. Cell, 2022 were tested for clonal hematopoiesis in Bolton et al. Nature Genetics, 2020 using the MSK-IMPACT targeted sequencing panel. CH mutations with variant allele frequency of at least 0.02 were detected in 19.5% of patients. Figure 11 B shows the 5 most commonly detected clonal hematopoiesis mutations from Figure 11 A are shown. Figure 11C shows exposure to TET2-mutant CH is associated with lower risk of having metastatic cancer in patients from Figure 11A as assessed by multivariate logistic regression adjusted for age, sex, smoking status, and chemotherapy treatment. Figure 10D shows exposure to TET2-CH is associated with significantly lower risk of having metastases in patients from Figure 11A with Non-Small Cell Lung and Breast Cancer, with a trend towards lower risk of metastases in colorectal and bladder cancer, as assessed by multivariate logistic regression adjusted for age, sex, smoking status, and chemotherapy treatment. Patients in Figure 11A with TET2-mutant CH have significantly few metastases detected on clinical imaging (Figure 11 E) and have fewer overall sites I organs involved with metastatic disease (Figure 11 F), p values from Wilcoxon Rank Sum Test. EXAMPLE 5

Applicant further sought to investigate the prevalence of CH among solid organ transplant (SOT) recipients (heart, lung, liver and kidney), study the association with specific CH-related genes and the impact on outcomes.

METHODS AND MATERIALS

Study Population

We conducted a retrospective study of 1 ,500 patients who underwent SOT at the Toronto General Hospital between 2005 and 2021. The inclusion criteria were patients aged 18 years or older with available biospecimens and complete clinical evaluation. Patients with active malignancies were excluded, as it is a criterion for solid organ transplant candidacy.

Data Collection

The electronic health records of the SOT recipients were reviewed to collect demographic data, medical history, laboratory assessments, date of SOT, transplant- related treatment at the time of the procedure, and the immunosuppressive regimen at one year post-SOT. Baseline characteristics, including demographic data and comorbidities, were collected as close as possible to the biospecimens collection date due to their relationship with CH mutations.

Follow-up and Outcomes

Patients were followed from the time of SOT procedure until the last visit at our institution or death. The following outcomes were evaluated: the first occurrence of acute cellular rejection, CMV infection, de novo post-transplant malignancy, CAV, and death.

Genetic Sequencing

Peripheral blood samples from patients who had provided consent during their visits to Toronto General Hospital. These samples were stored in the biobank of the Peter Munk Cardiac Centre. To construct the sequencing libraries, 100ng of DNA was utilized, and single molecule Molecular Inversion Probes (smMIP) were employed. The smMIPs were utilized to capture 35 genes known to be recurrently mutated in myeloid neoplasms. Sequencing was performed using the Illumina Novaseq platform, and an in-house computational pipeline was used to reduce artifacts and false-positive mutation calls. Alleles were filtered based on a P-value cut-off of 0.05 and were manually inspected based on several criteria, including base-pair change, annotation in COSMIC, minor allele frequency, and number of reads supporting the alternative allele. The resulting variants were analyzed and manually inspected to avoid selecting false positives.

Statistical analysis

The normality of all variables was assessed using the Shapiro-Wilk test, and both normal and non-normal continuous variables are reported as mean ± standard deviation or median (interquartile range). Student's t-test or Mann-Whitney test were used to evaluate differences among groups depending on the normality of the data. Categorical variables were assessed using chi-square test or Fisher's exact test. All analyses were performed using SPSS, version 25.0 (SPSS Inc., NY, USA), with a statistical significance level of 0.05 and a two-sided p-value.

RESULTS AND DISCUSSION

Out of the 1 ,500 patients enrolled, 782 have been sequenced as of the current date. Among these patients, 127 (16.2%) underwent heart transplant, 90 (11.5%) underwent lung transplant, 189 (24.2%) underwent kidney transplant, 374 (47.8%) underwent liver transplant, and 2 (0.3%) underwent lung-liver transplant. The average age of the entire cohort was 54.2±12.7 years, with a majority of male patients (52.9%). The age distribution varied significantly across organ groups (p<0.0001), with lung-liver transplant patients being the youngest (47±12.7), followed by heart (49.2±14.0), kidney (53.7±13.3), lung (54.4±15.1) and liver (56.1±10.8) transplant patients. Sex also differed among the organ groups (p=0.05), with all lung-liver transplant recipients being male, and a majority of heart (76.4%), kidney (76.2%), liver (66.5%), and lung (58.9%) transplant recipients being male. For a summary of the overall cohort characteristics, refer to Table 8.

CH was observed in 123 (15.7%) patients. CH prevalence was similar across the organ groups (Figure 12), except for kidney (8%) that was lower than heart (20%), lung (19%), and (liver 18%), p=0.007. Lung-liver showed a 50% of CH, but the low number of patients may explain this result. We than analyzed the specific mutated genes among patients with CH. In the literature, DNMT3A is the most common mutated gene in the general population, followed by TET2.[]3] In our cohort, DNMT3A was the most commonly mutated gene (n=45, 5.7%), followed by TET2 (n=40, 5.1%) and ASXL1 (n=20, 2.5%). Notably, DNMT3A was the most commonly mutated gene among heart transplant recipients (Figure 15) and among kidney recipients (Figure 17), while TET2 was the most common mutated gene among lung (Figure 16) and liver (Figure 18) recipients. These findings suggest that TET2 may play a role in lung and liver end-stage disease, but further clinical validation is required.

The overall mortality rate in our cohort was 18.3%. Mortality differed across the different SOT (p<0.0001), with the highest mortality observed in lung-liver recipients (50%), followed by lung (43.3%), heart (20.5%), liver (14.2%), and kidney (12.7%) recipients (Figure 19). We observed a trend in mortality according to the presence of CH (17.4% vs. 23.4%) (Figure 20). Among solid organ transplant recipients, those who received a heart transplant showed a higher mortality rate when developing CH (14% vs. 42%, p=0.002) with a trending shown for lung. CH did not affect the mortality of recipients of kidney or liver (Figure 21).

The study partial results shows that CH was observed in 15.7% of patients, with similar prevalence across most organ groups except for kidney, which had a lower prevalence. DNMT3A was the most commonly mutated gene among heart and kidney transplant recipients, while TET2 was the most common in lung and liver recipients. Heart transplant recipients had a higher mortality rate when developing CH.

Although preferred embodiments of the invention have been described herein, it will be understood by those skilled in the art that variations may be made thereto without departing from the spirit of the invention or the scope of the appended claims. All documents disclosed herein, including those in the following reference list, are incorporated by reference.

aPlus-minus are means±SD. bThe body-mass index is the weight in kilograms divided by the square of the height in meters.

Temporary mechanical

aPlus-minus are mean ± SD. bThe body-mass index is the weight in kilograms divided by the square of the height in metres. cPatients were classified according to the Society for Cardiovascular Angiography & Interventions. Briefly, Class B are patients at beginning of shock; Class C is classic cardiogenic shock; Class D is deteriorating 5 and failure to respond to initial interventions; and Class E is extreme shock on patients supported by multiple interventions who may be experiencing cardiac arrest and/or extracorporeal life support.

CH, clonal hematopoiesis; CMV, cytomegalovirus; EBV, Epstein-barr virus; HF, heart failure MCS, mechanical circulatory support; OHT, orthotopic heart transplant; VAD, ventricular assist device; VAF, variant allele frequency;

CAV, cardiac allograft vasculopathy; CH, clonal hematopoiesis; CMV, cytomegalovirus

tile 5. List of clonal hematopoiesis mutations detected among orthotopic heart transplant recipients.

:CHCVD_0117 DNMT3A chr2 25467124 25467124 Frame_Shift_lns indel T p.Tyr584fs 1599 36285 0.0440678

:CHCVD_0117 PPM1D chr17 58740549 58740549 Frame_Shift_Del indel G p.lle486fs 77 24796 0.00310534

:CHCVD_0117 PPM1D chr17 58740604 58740607 Frame_Shift_Del indel AACA p.Asn505fs 70 29465 0.0023757

:CHCVD_0117 PPM1D chr17 58740714 58740714 Frame_Shift_Del indel A p.Glu540fs 362 22820 0.01586328

:CHCVD_0117 PPM1D chr17 58740732 58740732 Frame_Shift_Del indel T p.Leu546fs 262 22819 0.01148166

:CHCVD_0117 TP53 chr17 7577526 7577526 Missense_Variant SNV A T p.Leu252His 278 15061 0.01845827

:CHCVD_0128 DNMT3A chr2 25469633 25469633 Missense_Variant SNV G A p.Arg379Cys 4474 62094 0.07205205

:CHCVD_0128 TP53 chr17 7577556 7577556 Missense_Variant SNV C T p.Cys242Tyr 422 40218 0.01049281

:CHCVD_0147 ASXL1 chr20 31023190 31023190 Missense_Variant SNV C A p.Ser892Tyr 228 36353 0.00627183

CHCVD_0149 DNMT3A chr2 25463196 25463197 Frame_Shift_Del indel TT p.Lys766fs 1027 37205 0.02760382

:CHCVD_0165 TP53 chr17 7577120 7577120 Missense_Variant SNV C G p.Arg273Pro 4705 12830 0.36671863

:CHCVD_0166 DNMT3A chr2 25463236 25463238 Frame_Shift_Del indel A p.Trp753fs 1226 55482 0.02209726

MCVD_0166 DNMT3A chr2 25463586 25463586 Missense_Variant SNV C T p.Gly699Asp 658 13363 0.04924044

HCVD_0166 DNMT3A chr2 25464455 25464455 Missense_Variant SNV G C p.Asp686Glu 145 12401 0.01169261

HCVD_0170 DNMT3A chr2 25463583 25463583 Missense_Variant SNV G A p.Pro700Leu 172 15467 0.01112045

HCVD_0200 PHF6 chrX 133549136 133549136 Stop_Gained SNV C T p.Arg274* 895 62494 0.01432137

:CHCVD_0210 SMC1A chrX 53431967 53431967 Stop_Gained SNV G A p.Arg725* 697 13878 0.05022338

:CHCVD_0227 DNMT3A chr2 25462078 25462078 Missense_Variant SNV G A p.Pro777Ser 547 19125 0.02860131

ARCHCVD_0227 PPM1D chr17 58740522 58740522 Frame_Shift_Del indel A p.Asn477fs 728 13283 0.0548069

ARCHCVD_0241 RUNX1 chr21 36252975 36252975 Missense_Variant SNV C T p.Leu129Leu 203 40261 0.0050421

ARCHCVD_0296 DNMT3A chr2 25458637 25458637 Stop_Gained SNV G A p.Gln846* 196 7986 0.02454295

ARCHCVD_0331 DNMT3A chr2 25470583 25470583 Stop_Gained SNV C T p.Trp297* 152 14952 0.01016586

ARCHCVD_0398 ASXL1 chr20 31022341 31022341 Missense_Variant SNV C T p.Thr609lle 5571 12858 0.43327112

ARCHCVD_0456 GATA2 chr3 128200154 128200154 Missense_Variant SNV C G p.Arg384Thr 127 47555 0.00267059

ARCHCVD_0492 TET2 chr4 106157803 106157810 Frame_Shift_Del indel AGAA p.Asn903fs 240 70735 0.00339295

ACCA

ARCHCVD_0563 BCOR chrX 39933121 39933121 Missense Variant SNV C T p.Gly493Asp 58 29158 0.00198916

ARCHCVD_0563 EZH2 chr7 148506185 148506185 Missense Variant SNV C G p.Glu725Gln 59 24362 0.0024218

ARCHCVD_0568 EZH2 chr7 148504787 148504787 Missense Variant SNV G C p.Ala736Gly 134 25452 0.00526481

ARCHCVD_0568 STAG2 chrX 123220456 123220456 Missense_Variant SNV G C p.Trp1038Leu 99 40520 0.00244324

:CHCVD_0585 TP53 chr17 7578278 7578278 Missense_Variant SNV G C p.Pro191Ala 118 31392 0.00375892

:CHCVD_0603 JAK2 chr9 5073739 5073739 Missense_Variant SNV C A p.His606Gln 9294 25742 0.36104421

:CHCVD_0614 TET2 chr4 106197039 106197039 Missense_Variant SNV C G p.Ser1791 Cys 146 29756 0.00490657

:CHCVD_0629 CEBPA chr19 33792987 33792987 Missense_Variant SNV G T p.Pro112Thr 128 130 0.98461538CHCVD_0636 DNMT3A chr2 25457243 25457243 Missense_Variant SNV G A p.Arg882Cys 6936 28768 0.02411012

0CHCVD_0636 DNMT3A chr2 25469096 25469096 Frame_Shift_Del indel G - p.Lys456fs 659 10067 0.00654601

2CHCVD_0636 DNMT3A chr2 25469162 25469162 Stop Gained SNV G C p.Tyr432* 897 91092 0.00984719

:CHCVD_0644 TET2 chr4 106155429 106155429 Missense_Variant SNV G T p.Lys110Asn 476 19776 0.02406958CHCVD_0657 BCOR chrX 39933039 39933039 Frame_Shift_Del indel G - p.Asn520fs 461 41910 0.01099976

:CHCVD_0673 PPM1D chr17 58740698 58740698 StopjGained SNV A T p.Lys535* 3230 36839 0.08767882

:CHCVD_0680 ASXL1 chr20 31021109 31021109 Missense_Variant SNV T A p.Ser370Thr 12555 20108 0.62437836

Table 7. Overall characteristics of the HCM cohort and between those with or without CH.

Abbreviations: CH, clonal hematopoiesis; HCM, hypertrophic cardiomyopathy; SCD, sudden cardiac death 1Body mass index calculated as weigh (kg)/height²(m)

Table A - SmMIP Probe List

ext pr logistic scor ext probe st ext probe st obe c SEQ lig probe st lig probe

>mip_key e chr art op opy ext probe sequence ID op _copy

4:55599221-55599390/20,24/- 0.944773 4 55599371 55599390 1 GCAGGACTGTCAAGCAGAGA 41 55599244 1

4:106155115-106155234/21,23/+ 0.928618 4 106155115 106155135 1 ACCAACCATGTTGAGGGCAAC 42 106155234 1

4:106155243-106155367/20,24/+ 0.976973 4 106155243 106155262 1 AAATGGAGACACCAAGTGGC 43 106155367 1

4:106155161-106155308/20,24/- 0.963051 4 106155289 106155308 1 TGGCTTCCCTTCATACAGGG 44 106155184 1

4:106155408-106155577/22,22/+ 0.954287 4 106155408 106155429 1 CTCTGGGCTCCTTCAGATCAAG 45 106155577 1

4:106155297-106155466/23,21/- 0.967386 4 106155444 106155466 1 GTCTTTCTCCATTAGCCTTTTGG 46 106155317 1

4:106155628-106155777/18,26/+ 0.954069 4 106155628 106155645 1 CCAGAGCTTCAGATTCTG 47 106155777 1

4:106155497-106155666/20,24/- 0.964361 4 106155647 106155666 1 ACTTTTCCCCTCCTGCTCAT 48 106155520 1

4:106155827-106155996/20,24/+ 0.947632 4 106155827 106155846 2 AGAAAACCACATCTCACATA 49 106155996 1

4:106155708-106155877/20,24/- 0.944218 4 106155858 106155877 1 ACTCATTAGTAGCCTGACTG 50 106155731 1

4:106156035-106156184/25,19/+ 0.927737 4 106156035 106156059 1 TACCTGTTCCTTTCAGAAACCAGAA 51 106156184 2

4:106155947-106156116/22,22/- 0.98082 4 106156095 106156116 1 GTTATTTTCTGCAGGAGATGGG 52 106155968 1

4:106156251-106156420/22,22/+ 0.902481 4 106156251 106156272 1 CTCAGTGTTCACTAAGGATTCC 53 106156420 1

4:106156143-106156312/25,19/- 0.903718 4 106156288 106156312 1 GCAATTGTGATGGTGGTGGTGGTGT 54 106156161 1

4:106156470-106156639/22,22/+ 0.946747 4 106156470 106156491 1 ACCACCTTCCCAGAGTCCTAAT 55 106156639 1

4:106156348-106156517/20,24/- 0.958324 4 106156498 106156517 1 GAAGGGCTGCATACATGTGT 56 106156371 1

4:106156694-106156863/20,24/+ 0.907492 4 106156694 106156713 1 TGATGAGAAACAAAGAGCAA 57 106156863 1

:106156579-106156748/20,24/- 0.965115 4 106156729 106156748 1 CGTGTTTGCTCCTTGTCTCG 58 106156602 1

4:106156916-106157085/23,21/+ 0.951204 4 106156916 106156938 1 CTGGAAATTCCAACATGCCTGGG 59 106157085 1

4:106156809-106156978/21,23/- 0.972677 4 106156958 106156978 1 GCTGTGTTGTTTTCTGGGTGT 60 106156831 1

4:106157149-106157318/21,23/+ 0.947906 4 106157149 106157169 1 CAACAAAGAGCAGATTCCCAA 61 106157318 1

4:106157036-106157205/20,24/- 0.962137 4 106157186 106157205 1 GTGCTGTTTCAACACTGGGG 62 106157059 1

4:106157399-106157568/18,26/+ 0.930675 4 106157399 106157416 1 ATGATCAGCAAAGAGAAG 63 106157568 1

4:106157269-106157438/18,26/- 0.968587 4 106157421 106157438 1 TTAGTCTGGCCAAAGAAT 64 106157294 1

4:106157597-106157766/21,23/+ 0.921979 4 106157597 106157617 1 CTTGTTCAAACAATACACACC 65 106157766 1

4:106157482-106157651/20,24/- 66 106157505 1

4:106157839-106158008/21,23/+ 0.951954 4 106157839 106157859 1 CTTGCTCAGCAAAGGTACTTG 67 106158008 1

4:106157718-106157892/22,22/- 0.959552 4 106157871 106157892 1 AGGCACAGGAAAAACATTTGCA 68 106157739 1

4:106158007-106158176/18,26/+ 0.886265 4 106158007 106158024 1 ACTGAGTCTTGCCATAGT 69 106158176 1

4:106157931-106158100/23,21/- 0.983485 4 106158078 106158100 1 TGTTTTCTGGTGGTGCTGTGTGC 70 106157951 1

4:106158223-106158378/21,23/+ 0.956903 4 106158223 106158243 1 GACCATAAGGCTCTTACTCTC 71 106158378 1

4:106158127-106158296/22,22/- 0.950701 4 106158275 106158296 1 GTCAAAACTGTGACTGGCCCTG 72 106158148 1

4:106158415-106158589/20,24/+ 0.882262 4 106158415 106158434 1 GAGTCACCTTCCAAATTACT 73 106158589 1

4:106158315-106158478/20,24/- 0.979383 4 106158459 106158478 1 GAGTCTTGACAGGTGTATCC 74 106158338 1

4:106162450-106162619/20,24/+ 0.88601 4 106162450 106162469 1 TAGTATAATTGAGGTCTAAA 75 106162619 1

4:106163956-106164125/22,22/+ 0.980266 4 106163956 106163977 4 TTGTATGTGTGTGTGTTTCTGT 76 106164125 1

4:106164761-106164930/21,23/+ 0.926757 4 106164761 106164781 1 TGTGTTTGGTGCGGGAGCGAG 77 106164930 1

4:106164674-106164843/20,24/- 0.873669 4 106164824 106164843 1 CGGGATTCCTTCCCACACCA 78 106164697 1

4:106164852-106165021/21,23/- 0.899251 4 106165001 106165021 1 CACGCTGAACTCTCTTCCTTT 79 106164874 1

4:106180720-106180889/24,20/+ 0.846203 4 106180720 106180743 1 TGCACAGCCTATATAATGCTATCC 80 106180889 1

4:106180786-106180955/20,24/- 0.931831 4 106180936 106180955 1 AGCGATTATACATCAGGAAG 81 106180809 1

ext pr logistic scor ext probe st ext probe st obe c SEQ lig probe st lig probe

>mip_key e chr art op opy ext probe sequence ID op _copy

4:106182895-106183049/19,25/+ 0.697024 4 106182895 106182913 1 AGAATTATTCACTTTATAC 82 106183049 1

4:106190771-106190940/20,24/+ 0.930131 4 106190771 106190790 1 AATATGAACACAGAGCACCA 83 106190940 1

4:106190690-106190859/21,23/- 0.810744 4 106190839 106190859 1 AGCACAGAAGTCCAAACATGC 84 106190712 1

4:106193771-106193940/22,22/+ 0.917879 4 106193771 106193792 1 GGATGAGCAGCTTCACGTTCTG 85 106193940 1

4:106193686-106193855/20,24/- 0.95666/ 4 106193836 106193855 3 1 1 1 1 1 1 Cl CCI CCI GAGC 1 1 86 106193709 1

4:106193946-106194115/20,24/+ 0.908902 4 106193946 106193965 1 GAAGCCAAGAAAGCTGCAGC 87 106194115 1

4:106193871-106194040/22,22/- 0.986116 4 106194019 106194040 1 TGTTTTGTACGTGATGGGGCTG 88 106193892 1

4:106196177-106196316/24,20/+ 0.915559 4 106196177 106196200 1 TTTCTGTTCTCTCTTACCCTGTCC 89 106196316 1

4:106196361-106196530/21,23/+ 0.913618 4 106196361 106196381 1 CCACCAATCCATACATGAGAC 90 106196530 1

4:106196262-106196431/20,24/- 0.95844 4 106196412 106196431 1 GATATCTGAAGTGTGTGAAG 91 106196285 1

4:106196561-106196730/20,24/+ 0.846784 4 106196561 106196580 1 CAATGCAATGGAAACCTATC 92 106196730 1

4:106196462-106196631/21,23/- 0.977129 4 106196611 106196631 1 GGCTGAGACTGGGGAGAATAG 93 106196484 1

4:106196781-106196950/20,24/+ 0.893805 4 106196781 106196800 1 GTTTCAGCAGTTGTACCATT 94 106196950 1

4:106196677-106196846/21,23/- 0.987067 4 106196826 106196846 1 GAGTGGGATAAGGAGGCAATT 95 106196699 1

4:106196887-106197056/21,23/+ 0.931081 4 106196887 106196907 1 ACCACCCAATCTGAGCAATCC 96 106197056 1

4:106196980-106197149/20,24/+ 0.893803 4 106196980 106196999 1 CATGTTCAACAGCTCTCTTC 97 106197149 1

4:106197193-106197362/24,20/+ 0.908112 4 106197193 106197216 1 CAACGATGAGGTCTGGTCAGACAG 98 106197362 1

:106197071-106197240/18,26/- 0.907301 4 106197223 106197240 1 TCAGGATCCAGAAAGCTC 99 106197096 1

4:106197400-106197569/20,24/+ 0.975927 4 106197400 106197419 1 ACATGGCTTGGCTCTTTGGG 100 106197569 1

4:106197289-106197458/24,20/- 0.959564 4 10619/435 10619/458 1 Cl I CC I C I 1 I C I CACGGGCI 1 1 1 1 101 106197308 1

4:106197523-106197692/20,24/- 0.923275 4 106197673 106197692 1 ACAAAAGGGGGTGATATCAT 102 106197546 1

5:170837475-170837644/22,22/- 0.943775 5 170837623 170837644 17 GGACAGCCAGATATCAACTGTT 103 170837496 1

7:140453073-140453242/20,24/+ 0.916227 7 140453073 140453092 1 ACCATCCACAAAATGGATCC 104 140453242 1

7:148504716-148504885/20,24/+ 0.944239 7 148504716 148504735 1 AGGGGGGAGGAGGTAGCAGA 105 148504885 1

7:148506108-148506277/22,22/- 0.949232 7 148506256 148506277 1 GCTCACTGACACCAGTGTGTCT 106 148506129 1

7:148506397-148506516/24,20/+ 0.969517 7 148506397 148506420 1 CCTACCTTTTGCATAGCAGTTTGG 107 148506516 1

7:148507392-148507561/23,21/- 0.965315 7 148507539 148507561 1 GTCAGGCTTGATCACCTTTATCC 108 148507412 1

7:148508689-148508858/20,24/- 0.923191 / 148508839 148508858 2 1 1 1 1 CACCC 1 CC 1 1 1 1 1 1 GA 109 148508712 1

7:148511097-148511266/23,21/+ 0.841123 7 148511097 148511119 1 TTACTGTCCCAATGGTCAGCGGC 110 148511266 1

7:148510995-148511164/20,24/- 0.869647 7 148511145 148511164 1 CTGGCTGTCCGAGAGTGTGA 111 148511018 1

7:148511955-148512124/20,24/- 0.889269 7 148512105 148512124 1 CTCTAACCATGTTTACAACT 112 148511978 1

7:148512532-148512701/22,22/- 0.917806 7 148512680 148512701 1 GCTCTCTGTTGGATTTGTAGCT 113 148512553 1

7:148516641-148516810/20,24/- 0./63635 / 148516/91 148516810 1 1 Al 1 AGAI 1 Cl 1 1 G 1 1 1 CA 1 114 148516664 1

7:148523639-148523808/20,24/+ 0.843345 7 148523639 148523658 1 CAGATTTAGCATTTGGTCCA 115 148523808 1

7:148523519-148523688/20,24/- 0.900594 7 148523669 148523688 1 ACTTCCTCCTGAATGTACCC 116 148523542 1

7:148526795-148526954/21,23/- 0.896884 / 148526934 148526954 1 1 1 1 1 1 1 I C I 1 1 IAGG I GGAAG 117 148526817 1

8:117864762-117864931/20,24/- 0.909931 8 117864912 117864931 1 TTACACCGCTTGTACCAGAA 118 117864785 1

8:117864807-117864976/23,21/- 0.85/98/ 8 11/864954 11/8649/6 1/ GAAAI 1 1 1 1 Cl 1 1 1 1 1 1 1 1 1 1 1 1 119 117864827 1

8:117866456-117866633/21,23/+ 0.779265 8 117866456 117866476 1 GAAGTAAAAATTCTGCAAACT 120 117866633 1

8:117866573-117866742/24,20/- 121 117866592 1

8:117868372-117868549/24,20/- 0.808009 8 11/868526 11/868549 31 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 ACAG 1 G 122 117868391 1

ext pr

Iogistic_scor ext probe st ext probe st obe c SEQ lig probe st lig probe

>mip_key e chr art op opy ext probe sequence ID op _copy

9:5069922-5070091/20,24/- 0.88135 9 5070072 5070091 1 AAGGACAAAAAAGACAGTAA 123 5069945 1

9:5073712-5073881/20,24/+ 0.965559 9 5073712 5073731 1 AGCAAGTATGATGAGCAAGC 124 5073881 1

10:112350147-112350316/21,23/+ 0.883234 10 112350147 112350167 1 TTTTCATTTCTGACAACTTAC 125 112350316 1

10:112350217-112350386/21,23/- 0.943637 10 112350366 112350386 1 TAAGCTATTCTTATTCCCTCT 126 112350239 1

10:112350706-112350875/22,22/+ 0.922256 10 112350706 112350727 1 CCTGAGTACCAATAAAGATTTG 127 112350875 1

10:112350813-112350982/20,24/- 0.959726 10 112350963 112350982 1 GTGTATAGTGCCTGGGCACT 128 112350836 1

10:112352791-112352960/22,22/+ 0.980092 10 112352791 112352812 1 CTGTGTTGTGATCTCTCTGTTG 129 112352960 1

10:112352887-112353056/21,23/- 0.892519 10 112353036 112353056 1 CGCCCAGCCAGATTATATGTT 130 112352909 1

10:112356126-112356295/20,24/+ 0.893075 10 112356126 112356145 1 ACAGACCTATTACATATGTT 131 112356295 1

11:32413487-32413656/20,24/+ 0.897861 11 32413487 32413506 1 GAAAAATAAATGTGAAGAAA 132 32413656 1

11:32414159-32414328/20,24/- 0.930567 11 32414309 32414328 1 TCAAATAGAATATGTGTCTT 133 32414182 1

11:32417866-32418035/20,24/+ 0.938676 11 32417866 32417885 1 GGTAAGCACACATGAAGGGG 134 32418035 1

11:32417752-32417921/20,24/- 0.91638 11 32417902 32417921 1 TCTTGTACGGTCGGCATCTG 135 32417775 1

11:32421472-32421637/20,24/+ 0.93191 11 32421472 32421491 1 TGGGGCCTGTCTGTGTGCTC 136 32421637 1

11:119148811-119148980/23,21/+ 0.851218 11 119148811 119148833 1 CTGTTAACATTTATAATTGCAGT 137 119148980 1

11:119148895-119149064/20,24/- 0.92696 11 119149045 119149064 1 TACCGAATTTTCCAAGGTTA 138 119148918 1

11:119149175-119149344/20,24/+ 0.895932 11 119149175 119149194 2 AGTATTTTCAGATGCATCTG 139 119149344 1

2:25378504-25378673/20,24/- 0.911124 12 25378654 25378673 1 GTACCTATGGTCCTAGTAGG 140 25378527 1

12:25380216-25380385/20,24/- 0.967652 12 25380366 25380385 1 TGCACTGTAATAATCCAGAC 141 25380239 1

12:25398165-25398334/20,24/- 0.933725 12 25398315 25398334 1 ATAAGGCCTGCTGAAAATGA 142 25398188 1

12:112888093-112888262/23,21/- 0.916866 12 112888240 112888262 3 CCATTCTTCTCTTTTAATTGCCC 143 112888113 1

12:112910715-112910880/22,22/+ 0.894139 12 112910715 112910736 1 CACGTAATAATATTGACTTTTC 144 112910880 1

12:112915411-112915580/20,24/- 0.966125 12 112915561 112915580 1 GGCTAGAAATGTATGGTCAG 145 112915434 1

12:112926198-112926363/20,24/- 0.918085 12 112926344 112926363 2 CATAAACTAAAAACAGAAAC 146 112926221 1

12:112926812-112926981/20,24/+ 0.957582 12 112926812 112926831 1 GATGTTTCCTTCGTAGGTGT 147 112926981 1

13:28592560-28592729/20,24/+ 0.919768 13 28592560 28592579 1 CACAAAATAGCCGTATAAAA 148 28592729 1

13:28602295-28602464/16,29/+ 0.881258 13 28602295 28602310 2 TTTTCGTGGAAGTGGG 149 28602464 1

13:28607990-28608155/20,24/- 0.927129 13 28608136 28608155 1 GCACGTACTCACCATTTGTC 150 28608013 1

13:28608205-28608374/20,24/+ 0.894916 13 28608205 28608224 1 CATTCCATTCTTACCAAACT 151 28608374 1

13:28608170-28608339/20,24/- 0.920908 13 28608320 28608339 1 GAAAGCCAGCTACAGATGGT 152 28608193 1

13:28608401-28608570/20,24/+ 0.891863 13 28608401 28608420 1 AGAGGAAAGAATAATGAATT 153 28608570 1

13:28609586-28609755/21,23/+ 0.98033 13 28609586 28609606 1 GTGGGGAATTCCTGATGGTGG 154 28609755 1

13:28609701-28609870/20,24/+ 0.946119 13 28609701 28609720 1 ACCCTTTTATGGCTTCACTC 155 28609870 1

13:28610048-28610217/20,24/+ 0.916878 13 28610048 28610067 1 AAGAGGCATCAATGTCCTTA 156 28610217 1

15:90631745-90631914/20,24/+ 0.801172 15 90631745 90631764 1 AAGAGGATGGCTAGGCGAGG 157 90631914 1

15:90631845-90632014/20,24/+ 0.93551 15 90631845 90631864 1 TGGTGATGGGCTTGGTCCAG 158 90632014 1

17:7572870-7573039/21,23/+ 0.981202 17 7572870 7572890 1 AGGGGAGGGAGAGATGGGGGT 159 7573039 1

17:7573943-7574112/22,22/- 0.910933 17 7574091 7574112 1 CAAACAATTGTAACTTGAACCA 160 7573964 1

17:7576792-7576961/24,20/- 0.847926 17 7576938 7576961 1 TTCACTTTTATCACCTTTCCTTGC 161 7576811 1

17:7577075-7577244/24,20/+ 0.980151 17 7577075 7577098 1 TTCTCTTCCTCTGTGCGCCGGTCT 162 7577244 1

17:7576963-7577132/21,23/- 0.924868 17 7577112 7577132 1 GCTTTGAGGTGCGTGTTTGTG 163 7576985 1

ext pr logistic scor ext probe st ext probe st obe c SEQ lig probe st lig probe

>mip_key e chr art op opy ext probe sequence ID op _copy

17:7577438-7577602/20,24/+ 0.897643 17 7577438 7577457 1 AGAGGCAAGCAGAGGCTGGG 164 7577602 1

17:7577529-7577693/22,22/- 0.959787 17 7577672 7577693 14 AAAAAAAAAAAAAAAGGCCTCC 165 7577550 1

17:7578169-7578338/23,21/+ 0.893158 17 7578169 7578191 1 AACCAGACCTCAGGCGGCTCATA 166 7578338 1

17:7578093-7578262/23,21/- 0.937736 17 7578240 7578262 1 GAGTGGAAGGAAATTTGCGTGTG 167 7578113 1

17:7578393-7578562/18,26/+ 0.843508 17 7578393 7578410 1 ATGGTGGGGGCAGCGCCT 168 7578562 1

17:7578334-7578453/18,26/- 0.833295 17 7578436 7578453 1 CATGGCCATCTACAAGCA 169 7578359 1

17:7578469-7578628/26,18/- 0.890436 17 7578603 7578628 1 CTGCCGTCTTCCAGTTGCTTTATCTG 170 7578486 1

17:7579238-7579407/20,24/+ 0.809488 17 7579238 7579257 1 CAAACAAAAGAAATGCAGGG 171 7579407 1

17:7579298-7579467/21,23/+ 0.74921 17 7579298 7579318 1 TCAGGGCAACTGACCGTGCAA 172 7579467 1

17:7579416-7579577/20,24/+ 0.784204 17 7579416 7579435 2 AGGAGGGGGCTGGTGCAGGG 173 7579577 1

17:7579495-7579664/21,23/- 0.900055 17 7579644 7579664 2 TGGGGACCTGGAGGGCTGGGG 174 7579517 1

17:7579802-7579971/24,20/- 0.864469 17 7579948 7579971 1 TCATGCTGGATCCCCACTTTTCCT 175 7579821 1

17:58740425-58740594/22,22/+ 0.952631 1 / 58 /40425 58 /40446 1 GCC I I C I CA A AA I I l l i I AG 176 58740594 1

17:58740303-58740472/20,24/- 0.827005 17 58740453 58740472 1 CTCTCGAGCTATCTCAGCTG 177 58740326 1

17:58740633-58740802/21,23/+ 0.979392 17 58740633 58740653 1 TGAAGATGTCAACTCCTGGCC 178 58740802 1

17:58740506-58740675/21,23/- 0.853213 17 58740655 58740675 1 TCAATTTCTTGGGCTTTCATT 179 58740528 1

17:58740833-58741002/20,24/+ 0.902941 17 58740833 58740852 1 ATGCGACGCAGACTTAGGGG 180 58741002 1

7:58740728-58740897/21,23/- 0.938281 17 58740877 58740897 1 GTTTTCCTGTGTTGATGAAGT 181 58740750 1

17:74732929-74733008/24,20/+ 0.924881 17 74732929 74732952 1 GGTCCCCGGCGGCTGTGGTGTGAG 182 74733008 1

18:42531843-42532012/21,23/+ 0.911291 18 42531843 42531863 1 CTCCCTAAAGGAAATCACGCT 183 42532012 1

19:13054585-13054754/20,24/+ 0.937952 19 13054585 13054604 1 AAGAAGACAAGAAACGCAAA 184 13054754 1

19:13054480-13054649/24,20/- 0.794174 19 13054626 13054649 1 ATCTTTGTCCTCATCATCCTCCTT 185 13054499 1

19:33792231-33792385/16,27/- 0.810719 19 33792370 33792385 12 GAAGGTGCTGGAGCTG 186 33792257 1

19:33792335-33792504/20,24/- 0.830437 19 33792485 33792504 1 AAGGCCAAGAAGTCGGTGGA 187 33792358 1

19:33792732-33792851/16,26/+ 0.652911 19 33792732 33792747 19 GCGGGTGCGGGTGCGG 188 33792851 1

19:33792942-33793051/16,24/- 0.849634 19 33793036 33793051 2 GGCCAAGGCGGCCGTG 189 33792965 1

19:33793045-33793154/16,29/+ 0.8992 19 33793045 33793060 10 CTTGGCCTTCTCCTGC 190 33793154 1

19:33793184-33793288/16,26/+ 0.876116 19 33793184 33793199 12 GGTGGGGCGGGAGGCT 191 33793288 1

20:31021052-31021221/21,23/+ 0.922229 20 31021052 31021072 1 GGCCTGAAACTGATGGCTGTG 192 31021221 1

20:31021242-31021411/22,22/+ 0.940116 20 31021242 31021263 1 CAGATCTCCGAACCAGAGCCAG 193 31021411 1

20:31021151-31021320/24,20/- 0.925719 20 31021297 31021320 1 TTTGCATCCTTAGCAACCCCTGCT 194 31021170 1

20:31021437-31021606/20,24/+ 0.888392 20 31021437 31021456 1 CCGAATTCCCAGTTGAGTCT 195 31021606 1

20:31021362-31021531/23,21/- 0.82328 20 31021509 31021531 1 CAGGCTAGGAATTCTGTCTGGAG 196 31021382 1

20:31021534-31021703/20,24/+ 0.939897 20 31021534 31021553 1 TCAGGAAACTGTGGATCAGG 197 31021703 1

20:31022183-31022352/22,22/+ 0.894333 20 31022183 31022204 1 TAGGTCAGATCACCCAGTCAGT 198 31022352 1

20:31022389-31022533/16,25/+ 0.740488 20 31022389 31022404 2 GAGGGGCGAGAGGTCA 199 31022533 1

20:31022292-31022441/20,24/- 0.670733 20 31022422 31022441 1 TCCGATGGCAGTGGTGGCCG 200 31022315 1

20:31022643-31022812/21,23/+ 0.806603 20 31022643 31022663 1 GGAACTGCCATGTCCAGAGCT 201 31022812 1

20:31022555-31022724/20,24/- 0.907715 20 31022705 31022724 1 CTGTAGCCCTCTGTAGTAGG 202 31022578 1

20:31022881-31023050/22,22/+ 0.931489 20 31022881 31022902 1 GTGAGTCTGGCACCACTTCCTG 203 31023050 1

20:31022782-31022951/23,21/- 0.91537 20 31022929 31022951 1 ACCATTGTCTGCAGGAACGGTGG 204 31022802 1

ext pr logistic scor ext probe st ext probe st obe c SEQ lig probe st lig probe

>mip_key e chr art op opy ext probe sequence ID op _copy

20:31023086-31023255/21,23/+ 0.933626 20 31023086 31023106 1 GCAGAACAGAGCATTTGATGA 205 31023255 1

20:31022984-31023153/23,21/- 0.932364 20 31023131 31023153 1 TATCACTTTCCCTCATAGGAGGG 206 31023004 1

20:31023328-31023497/20,24/+ 0.949461 20 31023328 31023347 1 CTGCATTGCCTGGGGATTTG 207 31023497 1

20:31023202-31023371/21,23/- 0.881999 20 31023351 31023371 1 AGGATCTAGACCCTCCTCAGC 208 31023224 1

20:31023421-31023590/20,24/- 0.918557 20 31023571 31023590 1 CTTTGTCACTGCAGCTTCTC 209 31023444 1

20:31023517-31023686/20,24/- 0.878099 20 31023667 31023686 1 ATCTGTCCTTGTAACCAGAC 210 31023540 1

20:31023708-31023877/22,22/+ 0.887733 20 31023708 31023729 1 TGGGTGTCTCGAGTATGTGCGG 211 31023877 1

20:31023619-31023788/20,24/- 0.904275 20 31023769 31023788 1 GGCTCTTGGCTGGTACTCAG 212 31023642 1

20:31023826-31023995/20,24/- 0.89 /669 20 310239 /6 31023995 1 GCCAC 1 1 1 1 1 1 1 CCAAGAC 213 31023849 1

20:31024004-31024173/20,24/+ 0.889572 20 31024004 31024023 1 TGGAAGCAGCCCCAGTTCTT 214 31024173 1

20:31024067-31024236/21,23/+ 0.894101 20 31024067 31024087 1 AGGCACTGGTCTTGCCAGGAT 215 31024236 1

20:31023931-31024100/20,24/- 0.934792 20 31024081 31024100 1 CTGGGTGGCCTCAATCCTGG 216 31023954 1

20:31024183-31024352/20,24/+ 0.897143 20 31024183 31024202 1 CTAGGAAACTGGAAGAAATG 217 31024352 1

20:31024301-31024470/24,20/+ 0.881533 20 31024301 31024324 1 CCCAGGAGATCTTACTACCTCGAG 218 31024470 1

20:31024409-31024578/20,24/+ 0.868986 20 31024409 31024428 2 AGGCCAAGGGAAGAAGCTTT 219 31024578 1

20:31024513-31024682/20,24/+ 0.949413 20 31024513 31024532 1 TTCCCAGTGGGAAGTTGGGA 220 31024682 1

20:31024623-31024792/20,24/+ 0.95695 20 31024623 31024642 1 GAGAAGACTTTTGTGGGGGG 221 31024792 1

0:31024736-31024905/23,21/+ 0.924311 20 31024736 31024758 1 CTTGCCCTTCTGGAAATTACCCC 222 31024905 1

20:31024855-31025024/21,23/+ 0.905752 20 31024855 31024875 1 TCCAACTGAGTTCCACCAGCT 223 31025024 1

20:31024965-31025134/20,24/+ 0.950131 20 31024965 31024984 1 CACAGTGCATCACTTTCCTT 224 31025134 1

20:57484366-57484525/18,26/- 0.944333 20 57484508 57484525 1 CAAGAAACCATGATCTCT 225 57484391 1

21:36164530-36164685/20,24/+ 0.734511 21 36164530 36164549 1 GGTTCGGGAGGCTGGGGTTG 226 36164685 1

21:36164619-36164747/21,23/+ 0.781897 21 36164619 36164639 2 ACCATGGAGAACTGGTAGGAG 1 1 36164747 1

21:36164705-36164815/20,24/+ 0.711885 21 36164705 36164724 1 TTGCGACGAGCCGGGGTAGG 228 36164815 1

21:36164717-36164857/23,21/+ 0.828908 21 36164717 36164739 1 GGGGTAGGGCGGCGGCAGGTAGG 229 36164857 1

21:36164802-36164956/19,25/+ 0.794232 21 36164802 36164820 1 GTCGGGGAGTAGGTGAAGG 230 36164956 1

21:36171528-36171697/21,23/- 0.841039 21 36171677 36171697 1 TCCATTGCCTCTCCTTCTGTG 231 36171550 1

21:36171646-36171815/22,22/- 0.8 /9815 21 361 /1 /94 361 /1815 1 CA 1 1 1 1 1 1 AAA 1 CCCACCCCAC 232 36171667 1

21:36206622-36206777/23,21/+ 0.865415 21 36206622 36206644 1 GGGAAGGTGTGTGCACATGGGGG 233 36206777 1

21:36206730-36206885/21,23/+ 0.735902 21 36206730 36206750 1 GGGTTAAAGGCAGTGGAGTGG 234 36206885 1

21:36206799-36206954/23,21/- 0.791705 21 36206932 36206954 15 TCTTCCCTCCCTCCTTCCCTCCC 235 36206819 1

21:36231732-36231901/22,22/- 0.873923 21 36231880 36231901 1 TTTTGTTCTCTATCGTGTCCCC 236 36231753 1

21:36252801-36252970/23,21/+ 0.943161 21 36252801 36252823 1 TGGGTTTGTTGCCATGAAACGTG 237 36252970 1

21:36252916-36253085/21,23/- 0.94378 21 36253065 36253085 1 ATCACTACACAAATGCCCTAA 238 36252938 1

21:36259108-36259222/16,29/+ 0.817091 21 36259108 36259123 15 CTGTCCTCCCACCACC 239 36259222 2

21:36259159-36259263/22,22/+ 0.706198 21 36259159 36259180 3 GTCTTGTTGCAGCGCCAGTGCG 240 36259263 1

21:44514729-44514898/22,22/- 0.933507 21 44514877 44514898 2 TTTCGCCGTGAGGAAGATGCGG 241 44514750 1

21:44524416-44524585/20,24/+ 0.94191 21 44524416 44524435 1 CAAACAAACCTGGCTAAACG 242 44524585 1

X:15833872-15834041/20,24/+ 0.979296 X 15833872 15833891 2 AATGGAGCAGTGCAGGAGGG 243 15834041 1

X:15833745-15833914/20,24/- 0.924197 X 15833895 15833914 2 GCTTGCGTCAGGGTCATAGT 244 15833768 1

X:15836657-15836826/21,23/- 0.93315 X 15836806 15836826 1 AACAGAAACAGAACAACAAAC 245 15836679 1

ext pr logistic scor ext probe st ext probe st obe c SEQ lig probe st lig probe

>mip_key e chr art op opy ext probe sequence ID op _copy

X:15838303-15838483/23,21/+ 0.712992 X 15838303 15838325 1 GCATATCATTTGA 1 1 1 1 1 GGTTT 246 15838483 1

X:39911340-39911509/20,24/+ 0.940705 X 39911340 39911359 1 GTACATGGTGGGTCCAGCTT 247 39911509 1

X:39911542-39911711/21,23/+ 0.932675 X 39911542 39911562 1 TTCTGCCTCTGCAATGGTGAC 248 39911711 1

X:39911448-39911617/20,24/- 0.941736 X 39911598 39911617 1 GAAATTGAAAATGTCCTCCC 249 39911471 1

X:39914595-39914764/20,24/+ 0.919934 X 39914595 39914614 1 AGACCATTTCTTGAACTTTG 250 39914764 1

X:39914691-39914860/24,20/- 0.966337 X 39914837 39914860 1 TGCCCAGCTTTGCCTGTTGCTTTT 251 39914710 1

X:39932843-39933012/24,20/+ 0.82704 X 39932843 39932866 1 TCCTGCTGGTTTTGGTGCCATCTG 252 39933012 1

X:39933079-39933248/20,24/+ 0.945629 X 39933079 39933098 1 GAGGGAGCAGTGCTGATGAT 253 39933248 1

X:39932964-39933133/20,24/- 0.933519 X 39933114 39933133 1 CTCCAGGAAATGGTTGTGCT 254 39932987 1

X:48649464-48649633/16, 29/+ 0.856993 X 48649464 48649479 14 TTTCTGTGTCTGAGGA 255 48649633 1

X:48649695-48649864/21, 23/+ 0.897556 X 48649695 48649715 1 TGGCCTACTACAGGGACGCTG 256 48649864 1

X:48649576-48649745/20, 24/- 0.823488 X 48649726 48649745 1 TGGAGTTACCTGGGGAGTGT 257 48649599 1

X:53431899-53432068/20,24/+ 0.892295 X 53431899 53431918 1 TGTGTGGATGGCCTTTGGAG 258 53432068 1

X:53432011-53432180/22,22/+ 0.897516 X 53432011 53432032 1 ATCTGCAGTCCATGGGCCTGAG 259 53432180 1

X:53432104-53432273/23,21/+ 0.897847 X 53432104 53432126 1 GCTAGGTGGTAAGGTGGTGGCTG 260 53432273 1

X:53432228-53432397/24,20/+ 0.904552 X 53432228 53432251 1 TTTCTCATCCCAGCGCCGTGCCTT 261 53432397 1

X:53432336-53432505/20,24/+ 0.904126 X 53432336 53432355 1 GGGGGAAGAGAGAAGAGGGG 262 53432505 1

;:53432548-53432717/23,21/+ 0.873273 X 53432548 53432570 1 ATCAATCACTAGCTTGGCCCCCT 263 53432717 1

X:53432438-53432607/22,22/- 0.912547 X 53432586 53432607 1 CAGGTGAAGCCTACAGATGAGA 264 53432459 1

X:53432775-53432944/23,21/+ 0.945673 X 53432775 53432797 1 GCCTGTCTTCTCCGAGTCCACAA 265 53432944 1

X:53432662-53432831/22,22/- 0.898153 X 53432810 53432831 1 ACCAAGGTTTTGGGCAAGAACA 266 53432683 1

X:123181234-123181403/20,24/+ 0.95047 X 123181234 123181253 1 TGGCACTAAATCTTAGCATT 267 123181403 1

X:123181157-123181326/20,24/- 0.9185 X 123181307 123181326 1 GCCTCTCATTGGCTCGTTTT 268 123181180 1

X:123182833-123183002/20,24/+ 0.820/83 X 123182833 123182852 1 GAAA I A 1 1 1 1 1 1 1 1 1 AC 269 123183002 1

X:123184006-123184184/21,23/+ 0.907704 X 123184006 123184026 1 TTATGCATCG 1 1 1 1 1 CCTTCC 270 123184184 1

X:123184910-123185079/20,24/+ 0.833242 X 123184910 123184929 1 GAAGTTGAAAATACATAGAG 271 123185079 1

X:123185026-123185195/22,22/+ 0.858971 X 123185026 123185047 1 AAGAGCTTAATTCCAAACTGGA TT 123185195 1

X:123185116-123185285/20,24/+ 0.932372 X 123185116 123185135 5 CTTTTCTCTTGCTTTCCTTT 273 123185285 1

X:123189951-123190120/21,23/- 0.874373 X 123190100 123190120 1 GCCTTAGAAAATGAGTAACAG 274 123189973 1

X:123220363-123220532/20,24/+ 0.871879 X 123220363 123220382 1 GTATCAAAGCTAACAGTTTC 275 123220532 1

X:123220475-123220644/20,24/- O.Tm. X 123220625 123220644 1 AAAGAGAATAAATTATATCC 276 123220498 1

X:133511649-133511818/20,24/+ 0.966325 X 133511649 133511668 1 TGTCAAGCTCAGTTGAACAG Til 133511818 1

X:133511601-133511770/20,24/- 0.96135 X 133511751 133511770 1 CGCTGCCACCTTCTGGTTTT 278 133511624 1

X:133527602-133527771/20,24/+ 0.867927 X 133527602 133527621 1 CTACCACTGTGCATTGCATG 279 133527771 1

X:133527477-133527646/20,24/- 0.939432 X 133527627 133527646 1 GGTTTCTCTCGTATTTGAGC 280 133527500 1

X:133527898-133528017/22,22/+ 0.864925 X 133527898 133527919 1 TTAGTTTGCTTACTAA 1 1 1 1 1 G 281 133528017 1

X:133547773-133547942/20,24/+ 0.896119 X 133547773 133547792 1 GAAATGTTAAGTAAGCTTGA 282 133547942 1

X:133547875-133548044/23,21/- 0.984411 X 133548022 133548044 17 AAACAAACAACAAAAAAACAAAA 283 133547895 1

X:133549006-133549180/27,27/- 0.875443 X 133549154 133549180 1 TGTTGCATAACAAATATAAAAACTACA 284 133549032

X:133551196-133551365/22,22/- 0.876924 X 133551344 133551365 1 GTTTAGGGAAATAGACAACTGT 285 133551217 1

mip_scan_start

I ig_pro be sequ en ce SEQ ID _position mip_name TCAGACTTCGGCCCACCC 286 43814917 MPL_001_Myeloid_Panel GTGTGGAGGGTAAGGGGGCAGGG 287 115256480 NRAS_001_Myeloid_Panel GTAGCCCGCTGACCTGATCCTGT 288 115258658 NRAS_002_Myeloid_Panel ACTGGGAAACCAAATACCCTGG 289 25457146 DNMT3A_001_Myeloid_Panel GCTGAAGGAGTATTTTGCGTGTGT 290 25457176 DNMT3A_002_Myeloid_Panel CCCGGGTTGTGCTGGCATCTGGCT 291 25458573 DNMT3A_003_Myeloid_Panel GCAGGGAGAAGGAAGGGCAGGAT 292 25459772 DNMT3A_004_Myeloid_Panel GCTCCTGGGCCTGGGGGGCTGT 293 25461989 DNMT3A_005_Myeloid_Panel GCGCATCATGCAGGAGGCGGTAGA 294 25463143 DNMT3A_006_Myeloid_Panel

GCGTTAGTGACAAGAGGGACATCT 295 25463209 DNMT3A_007_Myeloid_Panel GCTGTCCAGGGACAGAGGCAGACA 296 25463504 DNMT3A_008_Myeloid_Panel TTGGAGCCATCTCCCTGGCACCCT 297 25464530 DNMT3A_009_Myeloid_Panel GTCCATGCTGTGGGGCGCAG 298 25464427 DNMT3A_010_Myeloid_Panel GTGAGGGGTGCAGGCCCAAGAGGT 299 25466767 DNMT3A_011_Myeloid_Panel CTTCCTTAATGGCTGCCTGGGCAG 300 25467032 DNMT3A_012_Myeloid_Panel GCCTGGGGCGCGGTCTCGAGCT 301 25467013 DNMT3A_013_Myeloid_Panel

CCCTGGAACTGCTACATGTGC 302 25467139 DNMT3A_014_Myeloid_Panel GCTGTTGTGGCCTCCAGTGGT 303 25467404 DNMT3A_015_Myeloid_Panel GGTGAGTACCACCGAAGGGCCTCT 304 25468120 DNMT3A_016_Myeloid_Panel TGCCGTTGAGGCCGGCCCTTC 305 25468096 DNMT3A_017_Myeloid_Panel CCGCGCCTGCTCCTCGGATG 306 25468841 DNMT3A_018_Myeloid_Panel CACATGTCCGTGTACACTTCTTTG 307 25469013 DNMT3A_019_Myeloid_Panel TTCCCCCACCCTCCTTACAG 308 25469111 DNMT3A_020_Myeloid_Panel GTGACACGCCAGGGTTGGGGTTGT 309 25469530 DNMT3A_021_Myeloid_Panel GGCTGCCAAGGCCTCCACAGAG 310 25469407 DNMT3A_022_Myeloid_Panel CACCCACCCCATGCCTTGCAA 311 25469949 DNMT3A_023_Myeloid_Panel GCACTAGGAGGCCTGGAAGTTG 312 25469881 DNMT3A_024_Myeloid_Panel TTCCCCCACACCAGCTCCCCAA 313 25470458 DNMT3A_025_Myeloid_Panel GTGTCTTGGTGGATGACGGGC 314 25470544 DNMT3A_026_Myeloid_Panel

CGGGCCCCTGGTTTTCTT 315 25470939 DNMT3A_027_Myeloid_Panel AG GTAATTG GTGG ATTTACCTTTC 316 198266564 SF3Bl_001_Myeloid_Panel CTGGATATGTTTCATGGTTCT 317 198266438 SF3Bl_002_Myeloid_Panel GTGTTAAAGCCTTTATGGAAGGGT 318 198266754 SF3Bl_003_Myeloid_Panel GAAAGGACAGTCATGAGTTGGT 319 198267441 SF3Bl_004_Myeloid_Panel CTTATGGGCTGTGCCATCTTGCC 320 198267338 SF3Bl_005_Myeloid_Panel GGTGCCATTTGGTGATTTCC 321 209113087 IDHl_001_Myeloid_Panel TGCAGGAGAAGTCATCCCCCTTC 322 128200044 GATA2_001_Myeloid_Panel GGTGCCGGCTCTTCTGGCGG 323 128200685 GATA2_002_Myeloid_Panel CACTCATCAAGCCCAAGCGAAGAC 324 128202729 GATA2_003_Myeloid_Panel

GTCCAGGAACTGAGCAGAGGT 325 55589720 KIT_001_Myeloid_Panel

mip_scan_start

I ig_pro be sequ en ce SEQ ID _position mip_name GTGAATACACTATTAGGTTGGAGG 326 55599245 KIT_002_Myeloid_Panel GCCCACTGCCTGAGAGAGCTCAT 327 106155136 TET2_001_Myeloid_Panel GTAGAGGGTATTCCAAGTGTTTGC 328 106155263 TET2_002_Myeloid_Panel GTTCTGTCTGGCAAATGGGAGGTG 329 106155185 TET2_003_Myeloid_Panel TCTGTAGCCCAAGAAAATGCAG 330 106155430 TET2_004_Myeloid_Panel CGACTATTCTGGCTTCCCTTC 331 106155318 TET2_005_Myeloid_Panel TGGAACACACACATGGTGAACTCCTG 332 106155646 TET2_006_Myeloid_Panel CATTTGGTTGACTGCTTTCACCTG 333 106155521 TET2_007_Myeloid_Panel GTGAGTGAGGCCTGTGATGCTGAT 334 106155847 TET2_008_Myeloid_Panel GCACCATTAGGCATTAGCACTGCC 335 106155732 TET2_009_Myeloid_Panel CCAGCAGCAATTTGCAAGC 336 106156060 TET2_010_Myeloid_Panel GCAGCTGGCTTTGGAGGCAGCT 337 106155969 TET2_011_Myeloid_Panel CACCACCACTACCCCAACCAAA 338 106156273 TET2_012_Myeloid_Panel TGAACAGAATTCTTCACCA 339 106156162 TET2_013_Myeloid_Panel CCAATGTCAG AACACCTCAAG C 340 106156492 TET2_014_Myeloid_Panel GC I I I I I CCTTCTGAAGGAAGCTG 341 106156372 TET2_015_Myeloid_Panel CGTAATGAGGCATCACTGCCATCA 342 106156714 TET2_016_Myeloid_Panel .CACAATGGAACAGTCATTGTCCC 343 106156603 TET2_017_Myeloid_Panel CCCTCACACCAGGTGCACTTC 344 106156939 TET2_018_Myeloid_Panel GGGATTCCGCTTGGTGAAAACGA 345 106156832 TET2_019_Myeloid_Panel TCCCAGAGTTCACATCTCCCTCA 346 106157170 TET2_020_Myeloid_Panel GGAACTGGAGATGTTGGTCCACTG 347 106157060 TET2_021_Myeloid_Panel GAAATTCCCCTTATAGTCAGACCATG 348 106157417 TET2_022_Myeloid_Panel GGTTGTGTTTGTGCTGCCTGTTTATG 349 106157295 TET2_023_Myeloid_Panel GCTTTCAAGAACAGGAGCAGAAG 350 106157618 TET2_024_Myeloid_Panel GACATTATGAGTCTCGAACTCGCT 351 106157506 TET2_025_Myeloid_Panel CAGCAAACACAGCAACCCCAAAC 352 106157860 TET2_026_Myeloid_Panel GTGAAGAAGATCTTGCTTTGGG 353 106157740 TET2_027_Myeloid_Panel AATGTGCAGCAAAAGAGCATCATTGA 354 106158025 TET2_028_Myeloid_Panel GCAGCATGCTTTTGAGTGTCC 355 106157952 TET2_029_Myeloid_Panel CTTCTTCAGAAAAGACACCAACC 356 106158244 TET2_030_Myeloid_Panel CACAGCTTGCAGGTGGATTCTC 357 106158149 TET2_031_Myeloid_Panel CTTCAGATATGGGATTTTCCTTCT 358 106158435 TET2_032_Myeloid_Panel GCTGGGGTGTGGCTATCAAGTTCT 359 106158339 TET2_033_Myeloid_Panel GCAAAGGCACAGGGCAGATTAACG 360 106162470 TET2_034_Myeloid_Panel GCCTTTGGTCTTAAATCTTGGG 361 106163978 TET2_035_Myeloid_Panel CCAATCGCCGGTGTGCCTTGAAT 362 106164782 TET2_036_Myeloid_Panel CCCCCCACCCCAACCAAAACAAAA 363 106164698 TET2_037_Myeloid_Panel GCTCCGAGTAGAGTTTGTCAGCC 364 106164875 TET2_038_Myeloid_Panel TTTGCCAGAAGCAAGATCCC 365 106180744 TET2_039_Myeloid_Panel TTCTGGATCCAGCCCCTGACAGGC 366 106180810 TET2_040_Myeloid_Panel

mip_scan_start

I ig_pro be_sequ en ce SEQ ID _position mip_name GGCAGCAATTGTAACAACTTACTTG 367 106182914 TET2_041_Myeloid_Panel GAGGACAGCTTAGCAGCTGTTGAG 368 106190791 TET2_042_Myeloid_Panel GAAAACTCACTAGTATTTAGACC 369 106190713 TET2_043_Myeloid_Panel GTCAAGACTTGCCGACAAAGGA 370 106193793 TET2_044_Myeloid_Panel GTAAGACATTACAGCCTCAACTAC 371 106193710 TET2_045_Myeloid_Panel GCATTTGTAGATAAATGTGTTGTG 372 106193966 TET2_046_Myeloid_Panel GCCGAAAAGAACTCAGTACCTG 373 106193893 TET2_047_Myeloid_Panel CCCCAGCAGCAGCAGCCACA 374 106196201 TET2_048_Myeloid_Panel CCATGAACCCTTACCCTGGGCTT 375 106196382 TET2_049_Myeloid_Panel GCTGGGGCTGTGGTGGCTGCTTCT 376 106196286 TET2_050_Myeloid_Panel GCCAAGGTTTGGAAATAGCCAGAG 377 106196581 TET2_051_Myeloid_Panel CCTGCAGCTTGAGATGAGGTGGA 378 106196485 TET2_052_Myeloid_Panel GGTGAACATCATTCACCTTCTCAC 379 106196801 TET2_053_Myeloid_Panel GTGTATGGATGGGTGGTAGACTG 380 106196700 TET2_054_Myeloid_Panel GCTTTCCCACACAGCTAATGGGT 381 106196908 TET2_055_Myeloid_Panel GTGATGCTAATGGTCAGGAAAAGC 382 106197000 TET2_056_Myeloid_Panel TCACCCCACCAG G ATCTCCC 383 106197217 TET2_057_Myeloid_Panel iCAGTTCTATCATGGTTAAGAGCTGG 384 106197097 TET2_058_Myeloid_Panel CAGAGCCCACTTACCTGCGTTTCA 385 106197420 TET2_059_Myeloid_Panel G C AG CTC ACG CTTTG C AC AC 386 106197309 TET2_060_Myeloid_Panel GAAGTTTCATGTGGCTCAGCAGGC 387 106197547 TET2_061_Myeloid_Panel CCACAACACTTCATAGACATCA 388 170837497 NPMl_001_Myeloid_Panel CAGTAGATCTCATTTTCCTATCAG 389 140453093 BRAF_001_Myeloid_Panel CACAACAAAGCCTGCTGAAGATAG 390 148504736 EZH2_001_Myeloid_Panel GGGC I I I I I CTACTGGA I I GTG 391 148506130 EZH2_002_Myeloid_Panel GTAAGCACAGCCCAGTGAAT 392 148506421 EZH2_003_Myeloid_Panel GCTGGGAGGCAGTGAGTTCCT 393 148507413 EZH2_004_Myeloid_Panel GGCACTGATAACCTGTATTCAGGT 394 148508713 EZH2_005_Myeloid_Panel GGAGGTTCTTCACTCATCACC 395 148511120 EZH2_006_Myeloid_Panel GTAGTTAGCTATTTAGTGATGCAA 396 148511019 EZH2_007_Myeloid_Panel GCATGAGAACTAAATAGGTCTTTG 397 148511979 EZH2_008_Myeloid_Panel G C I I I G I I I I CA I I I G I I I I AG 398 148512554 EZH2_009_Myeloid_Panel GCAGAGGGTACTTGAGAGGACTTT 399 148516665 EZH2_010_Myeloid_Panel GTTTCTAAAAGGTTTCCATGTGTT 400 148523659 EZH2_011_Myeloid_Panel CGTTTTCATTTTCTATCTTTGTTG 401 148523543 EZH2_012_Myeloid_Panel GAGCCATATGCTTCTTCTCTTGG 402 148526818 EZH2_013_Myeloid_Panel TTGTTCTGTTGGAATAGTTCCTTG 403 117864786 RAD21_001_Myeloid_Panel GAGGACCAGCAACAGCAGCAT 404 117864828 RAD21_002_Myeloid_Panel GAATAATCACTAAGTTGGGCTCT 405 117866477 RAD21_003_Myeloid_Panel GGATCTGGCACCGCCCACCA 406 117866593 RAD21_004_Myeloid_Panel CCTTTAGATTTATACAGCAT 407 117868392 RAD21_005_Myeloid_Panel

mip_scan_start

I ig_pro be sequ en ce SEQ ID _position mip_name AGACTAGAAGGTTTGATTTATCTG 408 5069946 JAK2_001_Myeloid_Panel CAGGATCACAGCTAGGTGTCAGTG 409 5073732 JAK2_002_Myeloid_Panel CTTTCTACACATGCGTGGAAGTC 410 112350168 SMC3_001_Myeloid_Panel GCTGGTTTATTCCTTTTCGACGG 411 112350240 SMC3_002_Myeloid_Panel GTTAGATGTCAGGGATACAGCC 412 112350728 SMC3_003_Myeloid_Panel AGTAACCTCTCCAGGAAGATTCAT 413 112350837 SMC3_004_Myeloid_Panel CAGCTGGCCCGTGCTTTCACTA 414 112352813 SMC3_005_Myeloid_Panel GAGTCTTTCCAAACACATGTTTG 415 112352910 SMC3_006_Myeloid_Panel

GCAAAGCTCAATGAAAACCTGCGC 416 112356146 SMC3_007_Myeloid_Panel GCCTCGGCCCTAACAATGTGGGCA 417 32413507 WTl_001_Myeloid_Panel GCTGTGTTCCCTTGGGCTAGGGTT 418 32414183 WTl_002_Myeloid_Panel GTCTTGAGGGAGAGTGAGCACTGG 419 32417886 WTl_003_Myeloid_Panel GCAAACATGGTTCAAGAGCTCCTT 420 32417776 WTl_004_Myeloid_Panel

AGGCTCAGTGTGGCTCACAGTCGC 421 32421492 WTl_005_Myeloid_Panel GAGCCCTGTGGACACCTCATG 422 119148834 CBL_001_Myeloid_Panel GTTGGAATGTGGAGCCCATCTCAC 423 119148919 CBL_002_Myeloid_Panel GAGGCAAGGAGCAGAGGGAGCTCC 424 119149195 CBL_003_Myeloid_Panel

ACAGATCTGTTTTCTGCAAAATC 425 25378528 KRAS_001_Myeloid_Panel GACTGGGGAGGGCTTTCTTTGTGT 426 25380240 KRAS_002_Myeloid_Panel GCATATTACTGGTGCAGGACCATT 427 25398189 KRAS_003_Myeloid_Panel GTCCATTGGAAAGGGAGGCAA 428 112888114 PTPNll_001_Myeloid_Panel TCCGCTCAGTAATAGTCACTCT 429 112910737 PTPNll_002_Myeloid_Panel GGTCACATAAGTCCTGGACTGCTT 430 112915435 PTPNll_003_Myeloid_Panel

GGACAACAGAATCATTCATGGGGG 431 112926222 PTPNll_004_Myeloid_Panel GCGCAGGATTGAAGAAGAGCAGGT 432 112926832 PTPNll_005_Myeloid_Panel GGCCAGGTCTCTGTGAACACACTG 433 28592580 FLT3_001_Myeloid_Panel AAGGAGCATTAAAAATGTAAAACTCAAGT 434 28602311 FLT3_002_Myeloid_Panel GTGGAAGGACAGCAACAAAGATGC 435 28608014 FLT3_003_Myeloid_Panel

GCTTCAGAGATGAAATGATGAGTC 436 28608225 FLT3_004_Myeloid_Panel TCTGCAGCATTTCTTTTCCATTGG 437 28608194 FLT3_005_Myeloid_Panel GCAACAAAAGAGTGTCACTCAGCG 438 28608421 FLT3_006_Myeloid_Panel CTGCTCGACACCCACTGTCCAAA 439 28609607 FLT3_007_Myeloid_Panel GCTGTCATCAGATTGGAAGTTAGG 440 28609721 FLT3_008_Myeloid_Panel

CGTGTGAAATAAGCTCACTGGCTG 441 28610068 FLT3_009_Myeloid_Panel GCAGATGATGGGCTCCCGGAAGAC 442 90631765 IDH2_001_Myeloid_Panel GAGATAATAGTGGTCCCACTGCAG 443 90631865 IDH2_002_Myeloid_Panel GACAGAAGCAGGGAGGAGAGATG 444 7572891 TP53_001_Myeloid_Panel GCTGGGAAGGAGCCAGGGGGGA 445 7573965 TP53_002_Myeloid_Panel

GTCTAACACTCAAAATGCCG 446 7576812 TP53_003_Myeloid_Panel ACCAGGCTCCATCTACTCCC 447 7577099 TP53_004_Myeloid_Panel CCAAGGGTGCAGTTATGCCTCAG 448 7576986 TP53_005_Myeloid_Panel

mip_scan_start lig_probe_sequence SEQ ID _position mip_name GTAGTGGATGGTGGTACAGTCAGA 449 7577458 TP53_006_Myeloid_Panel GCGGCATGAACCGGAGGCCCAT 450 7577551 TP53_007_Myeloid_Panel CCTGGGGACCCTGGGCAACCA 451 7578192 TP53_008_Myeloid_Panel GTGAGCAGTAGGGGGG CTTTC 452 7578114 TP53_009_Myeloid_Panel GTTGAGGGCAGGGG AGTACTGTAGGA 453 7578411 TP53_010_Myeloid_Panel GGGCTGGAGAGACGACAGGGCTGGTT 454 7578360 TP53_011_Myeloid_Panel TTCCACACCCCCGCCCGG 455 7578487 TP53_012_Myeloid_Panel TTTCTGGGAAGGGACAGAAGATGA 456 7579258 TP53_013_Myeloid_Panel GTAGGAGCTGCTGGTGCAGGGGC 457 7579319 TP53_014_Myeloid_Panel G C ATC AAATC ATCC ATTG CTTG G G 458 7579436 TP53_015_Myeloid_Panel ACCCAGGTCCAGATGAAGCTCCC 459 7579518 TP53_016_Myeloid_Panel AAGGGCAGGCCCACCACCCC 460 7579822 TP53_017_Myeloid_Panel GCCTTCCAATTGGCCTTGTGCC 461 58740447 PPMlD_001_Myeloid_Panel AAAAAATTTATCCCAGAACTCAAC 462 58740327 PPMlD_002_Myeloid_Panel AGCCTGCAAGTCTCCCCACAACC 463 58740654 PPMlD_003_Myeloid_Panel CAA I l l i C I I C A AGTG GTT CT G G 464 58740529 PPMlD_004_Myeloid_Panel GATGTTGAAC I I l l i I I AAGGGGA 465 58740853 PPMlD_005_Myeloid_Panel iGTCTATG CTTCTTC ATC AG G G G 466 58740751 PPMlD_006_Myeloid_Panel AGCTCGCGGCCGTCCAGCAC 467 74732953 SRSF2_001_Myeloid_Panel TTTCTGCTCCCTGGACAACCCGG 468 42531864 SETBPl_001_Myeloid_Panel GGCCTGCCTCCAGGGCTGGACTGA 469 13054605 CALR_001_Myeloid_Panel CTTG CCCCCTGCCAG CCCTG 470 13054500 CALR_002_Myeloid_Panel GCAACTGCGCGTGAGGCGCGCGGCTGT 471 33792258 CEBPA_001_Myeloid_Panel TGACCGCCTGCGCAAGCGGGTGGA 472 33792359 CEBPA_002_Myeloid_Panel GCGGGGCTCCTGCTTGATCACCAGCG 473 33792748 CEPBA_003_Myeloid_Panel TCATGCCCGGGGGAGCGCACGGGC 474 33792966 CEBPA_004_Myeloid_Panel GCTGATGTCGATGGACGTCTCGTGCTCGC 475 33793061 CEBPA_005_Myeloid_Panel GCAGGTGGCTGCTCATCGGGGGCCGC 476 33793200 CEBPA_006_Myeloid_Panel GCCACCCGACAGCGAGATGGGCA 477 31021073 ASXLl_001_Myeloid_Panel TCCCCATCTGCCAGGCACATCC 478 31021264 ASXLl_002_Myeloid_Panel CCTGGGACACACAAGCCACT 479 31021171 ASXLl_003_Myeloid_Panel GAGCAGGCGGCCTCTGCATCCTTT 480 31021457 ASXLl_004_Myeloid_Panel GCCCTGCTGGGTCAGTCTTAG 481 31021383 ASXLl_005_Myeloid_Panel CACAGCCCACTAAAGAGGAGCCCA 482 31021554 ASXLl_006_Myeloid_Panel CGGGGTTGGACTGGCGCCAGGA 483 31022205 ASXLl_007_Myeloid_Panel GTGGTGATGGTGGTGAGGCCTGTGG 484 31022405 ASXLl_008_Myeloid_Panel GGTGGGGATGATCCGGGGGCATAT 485 31022316 ASXLl_009_Myeloid_Panel TGCCAGGCCTTGCCCCTACTGTC 486 31022664 ASXLl_010_Myeloid_Panel GTACACTTTCCAGGGGTGCTCGGG 487 31022579 ASXLl_011_Myeloid_Panel GGATCCTGTAAATGTGACCCCC 488 31022903 ASXLl_012_Myeloid_Panel G C AAG G CCTG G C ATG G CTG GT 489 31022803 ASXLl_013_Myeloid_Panel

mip_scan_start

I ig_pro be sequ en ce SEQ ID _position mip_name

GGTAGTGAAACAGCCCAAACCAG 490 31023107 ASXLl_014_Myeloid_Panel

GCTTGGCCAGTTCCTTTCTCT 491 31023005 ASXLl_015_Myeloid_Panel

GGAGACTCTGAAGCACTGAGTCCT 492 31023348 ASXLl_016_Myeloid_Panel

CGATGGGATGGGTATCCAATGCA 493 31023225 ASXLl_017_Myeloid_Panel

GTTGACAGTAACTGCCATTGCTGT 494 31023445 ASXLl_018_Myeloid_Panel

GGTGACCTTCAAAGTCAGAGGCTG 495 31023541 ASXLl_019_Myeloid_Panel

GTAGCTTGCCCCTAGAGAAGGT 496 31023730 ASXLl_020_Myeloid_Panel

GTGGGGCAGATTGGTTCCAATTGG 497 31023643 ASXLl_021_Myeloid_Panel

GCAACTGCATCACAAGTGGGTTAG 498 31023850 ASXLl_022_Myeloid_Panel

CCCTCCATCCAGTGACAAATCCCA 499 31024024 ASXLl_023_Myeloid_Panel

GCAGTTCTCTTCCTTTAGTTGTG 500 31024088 ASXLl_024_Myeloid_Panel

GCGAGCCATGGCTCTGGTCTTTTG 501 31023955 ASXLl_025_Myeloid_Panel

CCTCGTTTCTCATCTCCAAATGTG 502 31024203 ASXLl_026_Myeloid_Panel

AACCCTTCAGCGCCCCAGGC 503 31024325 ASXLl_027_Myeloid_Panel

GTGGGGTACAGACTCCAAGGGAAG 504 31024429 ASXLl_028_Myeloid_Panel

GCCGAGAACAGGAAAGCTACTGGG 505 31024533 ASXLl_029_Myeloid_Panel

GAAGGGGCTCAGTGAGCCTCTGGA 506 31024643 ASXLl_030_Myeloid_Panel

CTCTAGCTCTCCCACCTTTC 507 31024759 ASXLl_031_Myeloid_Panel

GCAGCACGGTGGAAAGCATCTCG 508 31024876 ASXLl_032_Myeloid_Panel

GCTCTGTGTATTGTGCCTTGTGGT 509 31024985 ASXLl_033_Myeloid_Panel

GAGGTCAATGGATCTCACCAAAGCCA 510 57484392 GNAS_001_Myeloid_Panel

GGTGGTAGGAGGGCGAGCTGGCTT 511 36164550 RUNXl_001_Myeloid_Panel

GCGGCGGCAGGTAGGTGTGGTAG 512 36164640 RUNXl_002_Myeloid_Panel

GGTGACCGGCGTCGGGGAGTAGGT 513 36164725 RUNXl_003_Myeloid_Panel

GCGGGGGTCGGAGATGGAGGG 514 36164740 RUNXl_004_Myeloid_Panel

GCGGAAGTGAGTAGGAGGTTGCGGA 515 36164821 RUNXl_005_Myeloid_Panel

GTCCAGGAGACTAGAGGTGCATG 516 36171551 RUNXl_006_Myeloid_Panel

ACGCCCATTTCACCTGGACGTG 517 36171668 RUNXl_007_Myeloid_Panel

GAGGCACGAGGGTTGGGCGTG 518 36206645 RUNXl_008_Myeloid_Panel

CGGGCTTGGTCTGATCATCTAGT 519 36206751 RUNXl_009_Myeloid_Panel

GCGGCGCACAGCCATGAGGGT 520 36206820 RUNXl_010_Myeloid_Panel

GGGCTGGTACACCCTCCAGGCT 521 36231754 RUNXl_011_Myeloid_Panel

CATCATTGCCAGCCATCACAG 522 36252824 RUNXl_012_Myeloid_Panel

GCTGAGCTGAGAAATGCTACCGC 523 36252939 RUNXl_013_Myeloid_Panel

GCAGAGGAAGTTGGGGCTGTCGGTGCGCA 524 36259124 RUNXl_014_Myeloid_Panel

GGCCAGCACCTCCACCATGCTG 525 36259181 RUNXl_015_Myeloid_Panel

GCCAGTGACGTGACTGAGCACA 526 44514751 U2AFl_001_Myeloid_Panel

CATGGAATATGTCAGCAGCATGAC 527 44524436 U2AFl_002_Myeloid_Panel

GCATGCGTGTGGAGGAGGGGACTG 528 15833892 ZRSR2_001_Myeloid_Panel

GGCCAATAGTTGAAAATTACTCAC 529 15833769 ZRSR2_002_Myeloid_Panel

AAATTCAGGAAAAGAAACCAGCC 530 15836680 ZRSR2_003_Myeloid_Panel

mip_scan_start

I ig_pro be sequ en ce SEQ ID _position mip_name

TTTCCTCAATTGTTCCACTGC 531 15838326 ZRSR2_004_Myeloid_Panel

GCTTCCAGGTCTTTGGAGCAAGAG 532 39911360 BCOR_001_Myeloid_Panel

GTAAAATGAAAAGTGCGCCCAAC 533 39911563 BCOR_002_Myeloid_Panel

GTAAGGAGCTGTTAGATCTGGTGG 534 39911472 BCOR_003_Myeloid_Panel

CGTTCTCAACAGCATCGTGCAGAG 535 39914615 BCOR_004_Myeloid_Panel

CTTATGGTGCTGACCCCACC 536 39914711 BCOR_005_Myeloid_Panel

TCGCCCAGTCCAATGCCTTG 537 39932867 BCOR_006_Myeloid_Panel

CATGTGGTCAGCTTTGGAAGCATC 538 39933099 BCOR_007_Myeloid_Panel

CAGCAGCGGAGTTCATCATGCCCG 539 39932988 BCOR_008_Myeloid_Panel

CAGGGGTTTTCTTCCCCTCTGGGCCTGAG 540 48649480 GATAl_001_Myeloid_Panel

GCTGGAAGCTTCTCAAATGGATG 541 48649716 GATAl_002_Myeloid_Panel

GGTGTGGAGGACACCAGAGCAGGA 542 48649600 GATAl_003_Myeloid_Panel

GCAGCTCTGCCTCTTTCCGTTTTG 543 53431919 SMClA_001_Myeloid_Panel

GCACTGCCTGTGGCTTACTTTC 544 53432033 SMClA_002_Myeloid_Panel

GCCTTCAGGTCACTGGCCCCA 545 53432127 SMClA_003_Myeloid_Panel

CCAGTACTGAGCCTGTCCAG 546 53432252 SMClA_004_Myeloid_Panel

G ACAAGGG CATTG CCACAAG CATA 547 53432356 SMClA_005_Myeloid_Panel

CTCACCTCCAG GTAGTCAAG 548 53432571 SMClA_006_Myeloid_Panel

GCCGCATTGCCTTTGGAGGCCA 549 53432460 SMClA_007_Myeloid_Panel

GCTTTTGGAAGCTGGCTCAGG 550 53432798 SMClA_008_Myeloid_Panel

GGGTCAGGCCAGTGTTCAAGGG 551 53432684 SMClA_009_Myeloid_Panel

GGCTATTGTGTGACCAACTTGGTC 552 123181254 STAG2_001_Myeloid_Panel

GGTGAAACTAATCTAACAGACACA 553 123181181 STAG2_002_Myeloid_Panel

GCAAGTTTGCATATTTCGTGGTGT 554 123182853 STAG2_003_Myeloid_Panel

AAGATGTGCCCTTCAGACTGCTT 555 123184027 STAG2_004_Myeloid_Panel

CCAGTCGGTTCAAGGTTAGTATTA 556 123184930 STAG2_005_Myeloid_Panel

GTGTCTATGACCCTTGACAAAG 557 123185048 STAG2_006_Myeloid_Panel

GCATATTTGCACTAATGTTCAGAT 558 123185136 STAG2_007_Myeloid_Panel

GAAATAAGCAGTAACAGGTGCTT 559 123189974 STAG2_008_Myeloid_Panel

ACCATGTCAGTCATTAGTGGAATC 560 123220383 STAG2_009_Myeloid_Panel

CCACCAGCTAGCAAAGAATTTCGG 561 123220499 STAG2_010_Myeloid_Panel

CCGGCAGCAACAGAGACCTTGAAA 562 133511669 PHF6_001_Myeloid_Panel

GCCACTTTAAGTCTCAAGAAATGC 563 133511625 PHF6_002_Myeloid_Panel

GCATTTCATCATCATCATAAAGGG 564 133527622 PHF6_003_Myeloid_Panel

GTATGTGACTTTCTAAGGCTGTAT 565 133527501 PHF6_004_Myeloid_Panel

CCACGTTTCAGCCACTTTTCAG 566 133527920 PHF6_005_Myeloid_Panel

GGGGAGGAAGAAAATGAAGCACGA 567 133547793 PHF6_006_Myeloid_Panel

GCCTGGTGTCACTAGGGCTGC 568 133547896 PHF6_007_Myeloid_Panel

ATGCAGGAAAATTAACATTCAGAATCC 569 133549033 PHF6_008_Myeloid_Panel GACTGCAAAGTGTACATTTCTG 570 133551218 PHF6_009_Myeloid_Panel

SEQ scan_target_sequence ID

CGGGGGCGGTACCTGTAGTGTGCAGGAAACTGCCACCTCAGCAGCAGCAGGCCCAGGACGGCGCTGAGGCCCAGCACTAGATGCAGAGCGGTCACCAAGGAGATCCAGGCTAGGAGACAAAAAGGG 571

GCCTTCGCCTGTCCTCATGTATTGGTCTCTCATGGCACTGTACTCTTCTTGTCCAGCTGTATCCAGTATGTCCAACAAACAGGTTTCACCATCTATAACCACTTGTTTTCTGTAAGAATCCTGGGG 572

AAATGACTGAGTACAAACTGGTGGTGGTTGGAGCAGGTGGTGTTGGGAAAAGCGCACTGACAATCCAGCTAATCCAGAACCACTTTGTAGATGAATATGATCCCACCATAGAGGTGAGGCCCAGTG 573

CCTTACACACACGCAAAATACTCCTTCAGCGGAGCGAAGAGGTGGCGGATGACTGGCACGCTCCATGACCGGCCCAGCAGTCTCTGCCTCGCCAAGCGGCTCATGTTGGAGACGTCAGTATAGTGG 574

TTTCTCCCCCAGGGTATTTGGTTTCCCAGTCCACTATACTGACGTCTCCAACATGAGCCGCTTGGCGAGGCAGAGACTGCTGGGCCGGTCATGGAGCGTGCCAGTCATCCGCCACCTCTTCGCTCC 575

CTAGTTCAGCAAAGTGAGGACCATTACTACGAGGTCAAACTCCATAAAGCAGGGCAAAGACCAGCATTTTCCTGTCTTCATGAATGAGAAAGAGGACATCTTATGGTGCACTGAAATGGAAAGGTA 576

ACAGTCTCTCTTCTGCCTCCTAGGCCGTTGGCATCCACTGTGAATGATAAGCTGGAGCTGCAGGAGTGTCTGGAGCATGGCAGGATAGCCAAGGTCAGCTCCAGCGTCTAGAACCTCTGCTGGGGG 577

CTCATCTTCAAACCGTCTCCTGTTTTGTAGTCCAACCCTGTGATGATTGATGCCAAAGAAGTGTCAGCTGCACACAGGGCCCGCTACTTCTGGGGTAACCTTCCCGGTATGAACAGGTTGGTGAAA 578

CTGGCCAAACCAAGGTTGCTGGCTATACCTCGAGAAATCGCGAGATGTCCCTCTTGTCACTAACGCCCATGGCCACCACATTCTCAAAGAGCCAGAAGAAGGGGCGATCATCTCCCTCCTTGGGCC 579

CTTCCGACCTCTCAGAGGGCACTGGCCGGCTCTTCTTTGAGTTCTACCGCCTCCTGCATGATGCGCGGCCCAAGGAGGGAGATGATCGCCCCTTCTTCTGGCTCTTTGAGAATGTGGTGGCCATGG 580

CCTACCGTAGAGGCCCTTGCGAGCAGGGTTGACGATGGAGAGGTCATTGCAGGGACTGCCCCCAATCACCAGATCGAATGGGCCCCACTCCTGGATCTGGGAGGATAAAGGCAACGTGATGGGCCT 581

AATGTAGCGGTCCACCTGAATGCCCAAGTCCTTCAGCACCAGGAGCCCTGCACCAGCCAGCAGACAGCACCGTTAC 582

GGACCGCTACATTGCCTCGGAGGTGTGTGAGGACTCCATCACGGTGGGCATGGTGCGGCACCAGGGGAAGATCATGTACGTCGGGGACGTCCGCAGCGTCACACAGAAGCATGTAT 583

ACCGCTGGGCCTGCATCTGACCTGTTGTGCTCACTGCTTAGGACCCTCCAAAGGTTTACCCACCTGTCCCAGCTGAGAAGAGGAAGCCCATCCGGGTGCTGTCTCTCTTTGATGGAATCGCTACAG 584

GGTCGTGGTTATTAGCGAAGAACATCTGGAGCCGGGAGGGCCAGTCCTCTCGCCGCCGCAGCAGCCCGTAGGTACCCTTGTGCCCGCACATGTAGCAGTTCCAGGGGT 585

GGCGGCGAGAGGACTGGCCCTCCCGGCTCCAGATGTTCTTCGCTAATAACCACGACCAGGAATTTGTGAGTGCTGG 586

CTTCCAGGTGCTTTTGCGTGGAGTGTGTGGACCTCTTGGTGGGGCCGGGGGCTGCCCAGGCAGCCATTAAGGAAGA 587

CTGTCTAGAACTGCTTTCTGGAGTGTGCGTACCAGTACGACGACGACGGCTACCAGTCCTACTGCACCATCTGCTGTGGGGGCCGTGAGGTGCTCATGTGCGGAAACAACAACTGCTGCAGGTGAG 588

ACCTTGCAGTTTTGGCACATTCCTCCAACGAAGAGGGGGTGTTCCAGGGTAACATTGAGGCTCCCACAGGAGATGCAGATGTCTGGAAAGCAGAGGGAGGGGATGG 589

ACATCTGCATCTCCTGTGGGAGCCTCAATGTTACCCTGGAACACCCCCTCTTCGTTGGAGGAATGTGCCAAAACTGCAAGGTAGGAGCACACCCACCCAGGAGAGG 590

GCCCCATGCCACACTAGGAGTGCCAGAGTTCCCAGGCAACAAACTTACCCTCAATGTTCCGGCACTTCTGCCGCACCTCGTACACCAGCCGCTCTGCAAGGGGAGGAGAGCTGGCGTCAGAGGAGG 591

GAAGCAGGCCAACTACCTCTTGTGCGCTCATCAATAATCTCCTTGACCTTGGGCTTCTCCGCTGTGCTCTTCCGGGGCTTTTTGGCTGGTGGAGGTGGTGCGTAGGCAGCTGCCTCAGGTTCCACC 592

TGCGTAGGCAGCTGCCTCAGGTTCCACCCACATGTCCGTGTACACTTCTTTGTAGGGATTCTTCTCTTCTGGAGGAGGAAAGCAGGTGCCAAGGTCAGTTACAGGCTGACAGGAAACTCCAGCCCC 593

CCCCCCAGGGCCCATTCAATCATGGGCTTGTTCTGCACCTCCACGGCCTTGGCAGTGTCACTCTCATCGCTGTCGTGGCACACCGGGAACAGCTTCCCCGCGCGGCTGCTGGCCACCTGGAGG 594

CTTCCAGCCTTCTGGCCCTAAGGGCCTGGAGCCACCAGAAGGTAAATGAGGGCACCCAGCTTTCTGGGACCCCTGCCCGCCAGGCAGATCCACACCAGGGCTGGGAAAGCCATGCTTAGGGAG 595

ACATGGGCTGCTTGTTGTACGTGGCCTGGTGGAACGCACTGCAAAACGAGCTCAGCGGCATCAGCTTCTCAACACACACCTGGGGGGACAAGCCAGGCCTTGTTTGCCGAGGCTTACACTTGCAAG 596

CCGCTGAGCTCGTTTTGCAGTGCGTTCCACCAGGCCACGTACAACAAGCAGCCCATGTACCGCAAAGCCATCTACGAGGTCCTGCAGGTGAGTGTCCCTGCTGGGAGCTCGGAGGAGGAGCCTAGA 597

ACCACTGAGAATTTGCCGTCTCCGAACCACATGACCCAGCGGGTGCCTTCAGCTGCTCGGCTCCGGCCCGTCATCCACCAAGACACAATGCGGCCTGGCCACCAGGAGAAGCCCCGCAGT 598

CCTCGTGACCACTGTGTAATGATTTCTGCTCCTTGGGGCTCCAGGACGGCCGGGGCTTTGGCATTGGGGAGCTGGTGTGGGGGAAACTGCGGGGCTTCTCCTGGTGGCCAGGCCGCATT 599

GGCATTCTTGTCCCCAGCATCGGACCCCACGGGCTCAGGCGTGGTAGCCACAGTGGGGGATGCGGGGTCAGTGGGCTGCTGCACAGCAGGAGGGCTGGCCTCCTCCACCTTCTGAGACTCCC 600

CCATAAGAGGAATAAGATACCCAATAGCCTTCAAGAAAGCAGCCAAACCCTATTTTTAAATAAAAAATATATGTACTTTAGTAATTTAGATTTATGTCGCCTTAACTTTAATGAAGATAAATCAAA 601

ATGCAGAATATGCCAACTACTATACTAGAGAAGTGATGTTAATCCTTATTCGAGAATTCCAGTCTCCTGATGAGGAAATGAAAAAAATTGTGCTGAAGGTAATTATTCCAGATTTGTTAATGTAAA 602

TTAAAACCTGTGTTTGGTTTTGTAGGTCTTGTGGATGAGCAGCAGAAAGTTCGGACCATCAGTGCTTTGGCCATTGCTGCCTTGGCTGAAGCAGCAACTCCTTATGGTATCGAATCTTTTGATTCT 603

AGGGCAGAGGCTACAACAGCAAAAGCTCTAGCTGTTGTGTTACGGACATACTCATCCATGTTATCTATATCAGGTCTCATGGTAGAGATCATAGTAGCCAGACCAGCAGCCTAAAATGTAAACAAA 604

TTTGCTGTTGTAGCCTCTGCCCTGGGCATTCCTTCTTTATTGCCCTTCTTAAAAGCTGTGTGCAAAAGCAAGAAGTCCTGGCAAGCGAGACACACTGGTATTAAGATTGTACAACAGATAGCTATT 605

ACTTACTTGATCCCCATAAGCATGACGACCTATGATGATAGGTTTTACCCATCCACTCACAAGCCGGGGGATATTTTTGCAGATAATGGCTTCTCTGAAGACCGTGCCACCCAGAATATTTCGTAT 606

CTAGGTTAACAGGCCACTGACCATGAAGAAGGAAGGGATCCAGACTCGGAACCGGAAGATGTCCAACAAGTCCAAGAAGAGCAAGAAAGGGGCGGAGTGCTTCGAGGAGCTGTCAAAGTGCA 607

CACAGGCGTTGCAGACAGGGTCCCCGTTGGCGTTTCGGCGCCATAAGGTGGTGGTTGTCGTCTGACAATTTGCACAACA 608

CAGAAGGCCGGGAGTGTGTCAACTGTGGGGCCACAGCCACCCCTCTCTGGCGGCGGGACGGCACCGGCCACTACCTGTGCAATGCCTGTGGCCTCTACCACAAGATGAATGGGCAGAACCGAC 609

TGACATATGGCCATTTCTGTTTTCCTGTAGCAAAACCAGAAATCCTGACTTACGACAGGCTCGTGAATGGCATGCTCCAATGTGTGGCAGCAGGATTCCCAGAGCCCACAATAGATTGGTATTTTT 610

SEQ scan_target_sequence ID

ATGGGTACTCACGTTTCCTTTAACCACATAATTAGAATCATTCTTGATGTCTCTGGCTAGACCAAAATCACAAATCTTTGTGATCCGACCATGAGTAAGGAGGATATTTCTGGCTGCCAAGTCTCT 611

AGACTAAGTCCATTCCTGATACCATCACCTCCCATTTGCCAGACAGAACCTCTGGCTACAAAGCTCCAGAATGGAA 612

ACTCTTTCAAAAGTTATTATGGAATACCCTGTATGAAGGGAAGCCAGAATAGTCGTGTGAGTCCTGACTTTACACAAGAAA 613

TATTCCATAATAACTTTTGAAAGAGTGCCACTTGGTGTCTCCATTTACTTCTGGATGAGCTCTCTCAGGCAGTGGGCTTCCATTCTGGAGCTTTGTAGCCAGAG 614

AAATTGAAACAAGACCAAAAGGCTAATGGAGAAAGACGTAACTTCGGGGTAAGCCAAGAAAGAAATCCAGGTGAAAGCAGTCAACCAAATGTCTCCGATTTGAGTGATAAGAAAGAATCTGTGAGT 615

TCTTGTTTCAATTTCTTGATCTGAAGGAGCCCAGAGAGAGAAGGTTCACTAACTGTGCGTTTTATTCCTCCATTTTGCAAACACTTGGAATACCCTCTACTTTCTTGTGTAAAGTCAGGACTCACA 616

AATGAGCAGGAGGGGAAAAGTGCTAATTACCATGACAAGAACATTGTATTACTTAAAAACAAGGCAGTGCTAATGCCTAATGGTGCTACAGTTTCTGCCTCTTCCG 617

TCAGAATCTGAAGCTCTGGATTTTCAGGCCCACTGCAGTTATGTGTTGAAAAACTGGTGAAATCTTTAACTGCATTTTCTTGGGCTACAGAACTCACAGATTCTTTCTTATCACTCAAATCGGAGA 618

AATGCCATTAACAGTCAGGCTACTAATGAGTTGTCCTGTGAGATCACTCACCCATCGCATACCTCAGGGCAGATCAATTCCGCACAGACCTCTAACTCTGAGCTGCCTCCAAAGCCAGCTGCAGTG 619

TTAATGGCATTTATGTGAGATGTGGTTTTCTGCACCGCAATGGAAACACAATCTGGATAATATTGAGACAGTGTTTTTTCCAGGAGTTCACCATGTGTGTGTTCCACGGAAGAGGCAGAAACTGTA 620

CAACTACAACAACAAAAATCAGTTTTTGAGATATGCCCATCTCCTGCAGAAAATAACATCCAGGGAACCACAAAGCTAGCGTCTGGTGAAGAATTCTGTTCAGGTT 621

CATATCTCAAAAACTGATTTTTGTTGTTGTAGTTGTTCTGGTTTCTGAAAGGAACAGGTATTTAGCATTGCAGCTAGTTTACTGGCATTATCAGCATCATCAGCATCACAGGCCTCACTCACCACT 622

TTTTCTGCCACTACCACACCACCACCACCATCACAATTGCTTCTTTCTCCCCCTCCTCCTCTTCCACAGGTTCCTCAGCTTCCTTCAGAAGGAAAAAGCACTCTGAATGGTGGAGTTTTAGAAGAA 623

GGTAGTGGCAGAAAAGGAATCCTTAGTGAACACTGAGCTTTGCTTGAAGTAAGCACCATTCATTTCATTTTGTTTTAAATACCGTTCAGAGCTGCCACCAGGAGCTTGCAAATTGCTGCTGGAACC 624

CCATCTACACATGTATGCAGCCCTTCTCCGATGCTTTCTGAAAGGCCTCAGAATAATTGTGTGAACAGGAATGACATACAGACTGCAGGGACAATGACTGTTCCATTGTGTTCTGAGAAAACAAGA 625

AGATGGATTAGGACTCTGGGAAGGTGGTGCCTCAGGTTTACCCTCTATTTTCACTTCCCTTAAAAGTGTTGTGTTACTTTGGTTGGGGTAGTGGTGGTGTTCTTCTAAAACTCCACCATTCAGAGT 626

GAGATTCTGAAGGGTCGAGACAAGGAGCAAACACGAGATCTTGTGCCCCCAACACAGCACTATCTGAAACCAGGATGGATTGAATTGAAGGCCCCTCGTTTTCACCAAGCGGAATCCCATCTAAAA 627

(CCCTTCAGAATCTCTTGCTCTTTGTTTCTCATCAACTGCTGGCAGTTGTCCTGTAGCTCTCCACTGCTACCAAAAATTGGTGGGTTATGCTTGAGGTGTTCTGACATTGGTCTTGTTTTCTCAGA 628

GGGCTCCCAAGGCAAGCTTACACCCAGAAAACAACACAGCTGGAGCACAAGTCACAAATGTACCAAGTTGAAATGAATCAAGGGCAGTCCCAAGGTACAGTGGACCAACATCTCCAGTTCCAAAAA 629

AAGCTTGCCTTGGGAGCCCCCCAGGCATGTTGGAATTTCCAGTGTATTGTTTGGAGGTCATTTGATTGGAGAGATTGGGTTGATACTGAAGAATTGATGGCAGTGATGCCTCATTACGTTTTAGAT 630

ACTGAAAAACTTATGTCCCCAGTGTTGAAACAGCACTTGAATCAACAGGCTTCAGAGACTGAGCCATTTTCAAACTCACACCTTTTGCAACATAAGCCTCATAAACAGGCAGCACAAACACAACCA 631

ACATAAGTTTTTCAGTTTGGGAATCTGCTCTTTGTTGAAAATGAAATCTAGTGCCACACAGTGACTGCACATGAGCTTTTGGTAAATGGTCTGTTTTGGAGAAGTGCACCTGGTGTGAGGGTTTTT 632

GATCATTCTTTGGCCAGACTAAAGTGGAAGAATGTTTTCATGGTGAAAATCAGTATTCAAAATCAAGCGAGTTCGAGACTCATAATGTCCAAATGGGACTGGAGGAAGTACAGAATATAAATCGTA 633

GATCCTTCTCTTTGCTGATCATTGTTGCTTTGGGGGTGAGGAAAAGTCTGGAGTATTTCCTCTTTATTCTTTATTTGTAATTTTTGCTGCTGTTGCTGGTTTTGAGGGAGATGTGAACTCTGGGAT 634

TAGTTTCAGAGAATAAAGAACAGACTACACATCCTGAACTTTTTGCAGGAAACAAGACCCAAAACTTGCATCACATGCAATATTTTCCAAATAATGTGATCCCAAAGCAAGATCTTCTTCACAGGT 635

ATTCTCTGAAACTAGGTGTGTATTGTTTGAACAAGAAACCTGTATTTTGCATGCACTTGATTTCATGGTCTGACTATAAGGGGAATTTCTACGATTTATATTCTGTACTTCCTCCAGTCCCATTTG 636

ATACATAACCATGCAAATGTTTTTCCTGTGCCTGACCAGGGAGGAAGTCACACTCAGACCCCTCCCCAGAAGGACACTCAAAAGCATGCTGCTCTAAGGTGGCATCTCTTACAGAAGCAAGAACAG 637

TGGTTATGTATCAAGTACCTTTGCTGAGCAAGTTGCGCAGCTTGTTGACCAGACATATCTTGGTTTCTATTTTTATATCCCTGTAGAACTGAAGCTTGTTGTGACTTCTGCTCCTGTTCTTGAAAGCACCT 638

CAGATGCACAGGCCAATTAAGGTGGAACCTGGATGCAAGCCACATGCCTGTATGCACACAGCACCACCAGAAAACAAAACATGGAAAAAGGTAACTAAGCAAGAGAATCCACCTGCAAGCTGTGAT 639

ATACAGGCATGTGGCTTGCATCCAGGTTCCACCTTAATTGGCCTGTGCATCTGACTATGGCAAGACTCAGTTTGGGGTTGCTGTGTTTGCTGCTGTTCTTGCTTCTGTAAGAGATGCCACCTTAGA 640

AAATCACAGAAGCAAGTAAAAGTTGAAATGTCAGGGCCAGTCACAGTTTTGACTAGACAAACCACTGCTGCAGAACTTGATAGCCACACCCCAGCTTTAGAGCAGCAAACAA 641

ACATTTCAACTTTTACTTGCTTCTGTGATTTGAGAGTAAGAGCCTTATGGTCAAATAACGACTTGGCGTGAAACTGCTTCAGATGCTGCTCCATGGTCTCAATGATGCTCTTTTGCTGCACATTAT 642

AGATACTCCTATAAAAAATTTATTGGATACACCTGTCAAGACTCAATATGATTTCCCATCTTGCAGATGTGTAGGTAAGTGCCAGAAATGTACTGAGACACATGGCGTTTATCCAGAATTAGCAAATTTAT 643

AATAAATTTTTTATAGGAGTATCTAGTAATTTGGAAGGTGACTCTATAAAATTATTGAGAACAGAAGCAGCTGTTCTTTTGGTTGGTGTCTTTTCTGAAGAAGTTGTTTGCTGCTCTAAA 644

ATAATAATCTTCTATTATCTCAACAGAGCAAATTATTGAAAAAGATGAAGGTCCTTTTTATACCCATCTAGGAGCAGGTCCTAATGTGGCAGCTATTAGAGAAATCATGGAAGAAAGGTAATTAAC 645

GGGTTTCTTTAAGGTTTGGACAGAAGGGTAAAGCTATTAGGATTGAAAGAGTCATCTATACTGGTAAAGAAGGCAAAAGTTCTCAGGGATGTCCTATTGCTAAGTGGGTAAGTGTGACTTGATAAA 646

CTGGCCACACCTGTGAGGCTGCAGTGATTGTGATTCTCATCCTGGTGTGGGAAGGAATCCCGCTGTCTCTGGCTGACAAACTCTACTCGGAGCTTACCGAGACGCTGAGGAAATACGGCACGCTCA 647

GGATGAGAATCACAATCACTGCAGCCTCACAGGTGTGGCCAGCTCGCTCCCGCACCAAACACAGTAGCTTCTCTTCACTGCTGCTTCTGCGAACCACCTGCGTGGATCACCATTCCATCCCAAACA 648

CAACCAAAGATTGGGCTTTCCTATCAGTGGCCGCAAAGAGGGGAGAGGCCCTGGGCTTCACTTACTCTTCATTCAAGGCACACCGGCGATTGGTGAGCGTGCCGTATTTCCTCAGCGTCTCGGTAA 649

ATAGCAATGAATTTGGTCTTTTGATTTTTCAGGAGAACTTGCGCCTGTCAGGGGCTGGATCCAGAAACCTGTGGTGCCTCCTTCTCTTTTGGTTGTTCATGGAGCATGTACTACAATGGATGTAAG 650

TAAACAAACCTCTTTTGGGTCATCCCCAAGCAGCTTAAACTTCCTTGGGATCTTGCTTCTGGCAAACTTACATCCATTGTAGTACATGCTCCATGAACAACCAAAAGAGAAGGAGGCACCACAGGT 651

SEQ scan_target_sequence ID

AGGAAGAGAAACTGGAGTCTCATTTGCAAAACCTGTCCACTCTTATGGCACCAACATATAAGAAACTTGCACCTGATGCATATAATAATCAGGTAAGTTTAAATAATCATT 652

GAGTGCCGTCTGGGTCTGAAGGAAGGCCGTCCATTCTCAGGGGTCACTGCATGTTTGGACTTCTGTGCTCATGCCCACAGAGACTTGCACAACATGCAGAATGGCAGCACATTGGTAAGTTGGGCT 653

AGTGACCCCTGAGAATGGACGGCCTTCCTTCAGACCCAGACGGCACTCTGGTGCTCTGTGTTCATATTCAATCTGAAAAATAAAAGTGTGTGTGAATGCGAAAGTAGTTAGTTTTACTCTTACACC 654

CCTTTATACAAAGTCTCTGACGTGGATGAGTTTGGGAGTGTGGAAGCTCAGGAGGAGAAAAAACGGAGTGGTGCCATTCAGGTACTGAGTTCTTTTCGGCGAAAAGTCAGGATGTTAGCAGAGCCA 655

CCACACTCCCAAACTCATCCACGTCAGAGACTTTGTATAAAGGCAGAACGTGAAGCTGCTCATCCTCAGGTTTTCCTCCAAATTCTCGATTGTCTTCTCTAGTGAGAGTGCATACCTGGTAGGGAA 656

TGAAAAGCTTTCCTCCCTGGAGAACAGCTCAAATAAAAATGAAAAGGAAAAGTCAGCCCCATCACGTACAAAACAAACTGAAAACGCAAGCCAGGCTAAACAGTTGGCAGGTAAATTTAATGTAAA 657

ACTTTTCCTTTTCATTTTTATTTGAGCTGTTCTCCAGGGAGGAAAGCTTTTCAGCTGCAGCTTTCTTGGCTTCTAGTTTCCTTTGTCGGCAAGTCTTGACTGGCTCTGCTAACATCCTGACTTTTC 658

ACAGAACTTTTGCGACTTTCAGGACCAGTCATGCAGCAGTCCCAGCAGCCCCAGCCTCTACAGAAGCAGCCACCACAGCCCCAGCAGCAGCAGAGA 659

GGCCCAATCCAGTTAGTCCTTATCCAAACTCTTCACACACTTCAGATATCTATGGAAGCACCAGCCCTATGAACTTCTATTCCACCTCATCTCAAGCTGCAGGTTCATATTTGAATTCTTCTAATC 660

AGTTTGGATAAGGACTAACTGGATTGGGCCGTCTCATGTATGGATTGGTGGATCCAGAAGCAGAATAAGAGTTGACAGACTCTGTCTGAGGGTGATGTGGCTGCTGCTGCTGGGGTCTCTGCTGCT 661

AGTGGACAACTGCTCCCCATATCTGGGTTCCTATTCTCCCCAGTCTCAGCCGATGGATCTGTATAGGTATCCAAGCCAAGACCCTCTGTCTAAGCTCAGTCTACCACCCATCCATACACTTTACCA 662

GAACCCAGATATGGGGAGCAGTTGTCCACTGATAGGTTTCCATTGCATTGATATGATGGATATTGGGTATTCTGATTCAAAAGCCCAGGGTAAGGGTTCATGGGATTAGAAGAATTCAAATATGAA 663

AGACCAAATGTACATCATGTAGGGAAATTGCCTCCTTATCCCACTCATGAGATGGATGGCCACTTCATGGGAGCCACCTCTAGATTACCACCCAATCTGAGCAATCCAAACATGGACTATAAAAAT 664

TCCCTACATGATGTACATTTGGTCTAATGGTACAACTGCTGAAACCATCTCCCTGCATATTTTGGTTTCCATAACCTAAGTATTTAGATGTAAAACTCTGGCTATTTCCAAACCTTGGCTGGTAAA 665

AAACATGGACTATAAAAATGGTGAACATCATTCACCTTCTCACATAATCCATAACTACAGTGCAGCTCCGGGCATGTTCAACAGCTCTCTTCATGCCCTGCATCTCCAAAACAAGGAGAATGACAT 666

ATGCCCTGCATCTCCAAAACAAGGAGAATGACATGCTTTCCCACACAGCTAATGGGTTATCAAAGATGCTTCCAGCTCTTAACCATGATAGAACTGCTTGTGTCCAAGGAGGCTTACACAAATTAA 667

CGAGCAGAGCTTTCTGGATCCTGACATTGGGGGAGTGGCCGTGGCTCCAACTCATGGGTCAATTCTCATTGAGTGTGCAAAGCGTGAGCTGCATGCCACAACCCCTTTAAAGAATCCCAATAGGAA 668

GCTCGCTGTCTGACCAGACCTCATCGTTGTCCTCTGCACCAGAAGCCACACCCTGGACTAGTGCCAATGGCTGCTTTTCCTGACCATTAGCATCACTTAATTTGTGTAAGCCTCCTTGGACACAA 669

AAGCCAAAATGGCTGAAAAAGCCCGTGAGAAAGAGGAAGAGTGTGAAAAGTATGGCCCAGACTATGTGCCTCAGAAATCCCATGGCAAAAAAGTGAAACGGGAGCCTGCTGAGCCACATGAAACTT 670

CAGCCATTTTGGCTTCCCAAAGAGCCAAGCCATGTTTTGGCTCATTCATGCTCTTATGCTGGTAAAAGACGAGGGAGATCCTGGTGGGGTGATTCCTATTGGGATTCTTTAAAGGGGTTGTGGCAT 671

ATATATCTGTTGTAAGGCCCTGTGACCCGAGTGAAGGCATATGGAGATGTAGTTACTGTGGAGTCTGTGGTCACGGACATGGTCCTTTCGGCAAGAGACTTGATGAAACGCAGGTAAGTGGGCTCT 672

ACAGAAATGAAATAAGACGGAAAATTTTTTAACAAATTGTTTAAACTATTTTCTTAAAGAGACTTCCTCCACTGCCAGAGATCTTGAATAGCCTGGAAAAAAAAAAAAAGAAATGTGGTTAAGGAA 673

AGACAACTGTTCAAACTGATGGGACCCACTCCATCGAGATTTCACTGTAGCTAGACCAAAATCACCTATTTTTACTGTGAGGTCTTCATGAAGAAATATATCTGAGGTGTAGTAAGTAAAGGAAAA 674

TGTCAAGGGATTTCCATTTCTCTTTCGATGCCGACATACTTCAGGGCATCAGCCTGGCTGTATCTGAAACAACAGGAAGGAGATGTCCGCTGGATGGCCACCCATCCAACATGTGCTGAGACTTAA 675

CTTTGCAGTTATGATGGTTAACGGTGATCACAGGATAGGTATTTTTGCCAAGAGAGCCATCCAGACTGGCGAAGAGCTGTTTTTTGATTACAGGTTGGTAAAGTACATTTCTAGCATGATCTCTAA 676

ATTTACCGAATGATTTGCAAAACGAATTTTGTTACCCTTGCGGGTTGCATCCACCACAAAATCTAAAAAGAAAAAA 677

AAAAGAATTTTCTCCTGTGTCTTTCTTTTTAGATTATTTCTCAAGATGAAGCTGACAGAAGAGGGAAAGTGTATGATAAATACATGTGCAGCTTTCTGTTCAACTTGAACAATGGTATGTTTCAGA 678

TGATGTGATTGTGTTTTATTCTCTAGCATCTATTGCTGGCACCATCTGACGTGGCAGGCTGGGGGATTTTTATCAAAGATCCTGTGCAGAAAAATGAATTCATCTCAGAATACTGTGGAGAGGTAA 679

TCCACAAGTAAGACAGAGGTCAGGGTCACACTCTCGGACAGCCAGGTAGCACGGGCACTGCTTGGTGTTGCACTGTGCTTTGCAGCGGCATCCCGGAAAGCGGTTTTGACCTTCAGAGAGAGGTTT 680

CCCTGACCTCTGTCTTACTTGTGGAGCCGCTGACCATTGGGACAGTAAAAATGTGTCCTGCAAGAACTGCAGTATTCAGCGGGGCTCCAAAAAGGTGAGCAACAAGTCACTTCTGGAAGATTGTTT 681

ATCAACCCTGTGATCATCCACGGCAGCCTTGTGACAGTTCGTGCCCTTGTGTGATAGCACAAAATTTTTGTGAAAAGTTTTGTCAATGTAGTTCAGAGTGTAAGTATTTGTTGCTTTGATGCAATT 682

TCCCGCAGAAATTTGGTTTAATTTTCTTTGTGTTTTTGCAGGTTGTGGGCTGCACACTGCAGAAAGATACAGCTGAAAAAGGGTTAGCATCTTTCCATTCCTCTCATTATTAGCTTAACAATATCT 683

TTATTTTGCAGCTTTTCATGCAACACCCAACACTTATAAGCGGAAGAACACAGAAACAGCTCTAGACAACAAACCTTGTGGACCACAGTGTTACCAGCATTTGGTAAGACTTAGTGCCTAATTATT 684

TCTATGTTGGGGGTACATTCAGGAGGAAGTGCGCCTGGGAGCTGCTGTTCGGTGAGTTCTTTATATCTGACATTAACCAAGAAAAATTTAAGTAAACATGAAACAAAAATCACTTTTTTGAAAACA 685

CCAACATAGATGGACCAAATGCTAAATCTGTTCAGAGAGAGCAAAGCTTACACTCCTTTCATACGCTTTTCTGTAGGCGATGTTTTAAATATGACTGCTTCCTACATCGTAAGTGCAATTATTGTA 686

ATGAAACTGTTTTACATAACATTCCTTATATGGGAGATGAAGTTTTAGATCAGGATGGTACTTTCATTGAAGAACTAATAAAAAATTATGATGGGAAAGTACACGGGGATAGAGGT 687

GACCTTAGAAAAAGGAGGAAAGGAGGAGAGGCAGATAATTTGGATGAATTCCTCAAAGAATTTGAAAATCCAGAGGTTCCTAGAGAGGACCAGCAACAGCAGCATCAGCAGCGTGATGTTATCGGT 688

TAATAGCTCTTTACACGCTGTCTTACACCGCTTGTACCAGAAGACCTTAGAAAAAGGAGGAAAGGAGGAGAGGCAGATAATTTGGATGAATTCCTCAAAGAATTTGAAAATCCAGAGGTTCCTAGA 689

ATATTACCTTCAGTAGTCTGTTATTCCACAAAGGCTGAGCAGGTAAAGAAAACAGTTTTTCTACTCCTCCTGTCTCTTTCCACATCATCAATTTCTTGGTGGGCGGTGCCAGATCCAAAGTAGTAACAATATCT 690

TATCATTCCAGTTAAAGAAACAAAAGCCAAGAGGAAGAGGAAGCTAATTGTTGACAGTGTCAAAGAGTTGGATAGCAAGACAATTAGAGCCCAACTTAGTGATTATTCAGATATTGTTACTACTTT 691

GGTGGGCCTGATAGTCCTGATTCAGTGGATCCCGTTGAACCAATGCCAACCATGACTGATCAAACAACACTTGTTCCAAATGAGGAAGAAGCATTTGCATTGGAGCCTATTGATATAACTGGTAAGCATATGAA 692

SEQ scan_target_sequence ID

TGAGTATCTAATGACTTACAAATATCAAATCTTCATTTCTGATTTTGTGAAACACCATTTGGTTCATATGAGTAGGCCTCTGTAATGTTGGTGAGGTTGGTACATCAGAAACACCATTCGTTCTGA 693

TTTCTCACAAGCATTTGGTTTTAAATTATGGAGTATGTGTCTGTGGAGACGAGAGTAAGTAAAACTACAGGCTTTCTAATGCCTTTCTCAGAGCATCTGTTTTTGTTTATATAGAAAATTCAGTTT 694

AGGCCATTTTAAATGGAATAGACAGCATAAACAAAGTGCTAGACCACTTCCGTCGAAAAGGAATAAACCAGCATGTTCAAAATGGCTATCATGGTATTGTAATGAATAACTTTGAATGTGAACCAG 695

TCTAAAAATGCTAAATATCAAGCAAAAGCTTTAACCTGTTTCCAGCAGTGACTTCCACGCATGTGTAGAAAGCTGGTTCACATTCAAAGTTATTCATTACAATACCATGATAGCCATTTTGAACAT 696

TCTTACTCTGTTTATATTTAGGTTATTTTATCACATTGTTGATTCAGATGAAGTCAGCACGAAGATTTTAATGGAGTTTAATAAAATGAATCTTCCTGGAGAGGTTACTTTTCTGCCTCTTAACAA 697

AGCATGTGTTAGATTATGTGATAAAAAATAACATTATAAAAGAGAAATACACCTTATCACACAATGACTCACATTGGTTTCAGGATAGGCTGTATCCCTGACATCTAACTTGTTAAGAGGCAGAAA 698

ACAAAATTTCATTTTTAGGATGCTATTCCTATGATCAGCAAACTGAGGTACAATCCCAGATTTGACAAAGCTTTCAAACATGTGTTTGGAAAGACTCTTATTTGTCGTAGCATGGAAGTTTCAACC 699

TTAAATGATTTGTTAGAATTTATCTGTTTAAAGCTAAGAATTAGTATTACAAACCTTCCAAAGTAATACAGTCCATAGTGAAAGCACGGGCCAGCTGGGTTGAAACTTCCATGCTACGACAAATAA 700

TTGTTTATAGGTGACCAAGTCAGCCATCGGGGTGCTCTAACTGGGGGTTATTATGACACAAGGAAGTCTCGACTTGAATTGCAAAAAGATGTTAGAAAAGCAGAAGAAGAACTAGGTGAACTTGAA 701

AGTTTACGCACTTGTTTTACCTGTATGAGTCCTGGTGTGGGTCTTCAGGTGGTCGGACCGGGAGAACTTTCGCTGACAAGTTTTACACTGGAATGGTTTCACACCTAAATGGACAGAGAAGGTCTA 702

CCCCAAGGTGAGAAACCATACCAGTGTGACTTCAAGGACTGTGAACGAAGGTTTTCTCGTTCAGACCAGCTCAAAAGACACCAAAGGAGACATACAGGTTTGTAGGTTCACTTCTCATTGCTGGCA 703

CGTTTCTCACTGGTCTCAGATGCCGACCGTACAAGAGTCGGGGCTACTCCAGGCACACGTCGCACATCCTGCAGGCAGAGAGTAAGAGGAAGGGAGGCTTTAAGCCACATGTGAACATTCACGTAG 704

AGACCAGTGAGAAACGCCCCTTCATGTGTGCTTACCCAGGCTGCAATAAGAGATATTTTAAGCTGTCCCACTTACAGATGCACAGCAGGAAGCACACTGGTAAGTGTGCCCGCTGTCCAGTCTTGG 705

ACCTGAATGCCTCTGAAGACACCGTGCGTGTGTATTCTGTATTGGGCTCCGCAGAGGATGGGCGTTGTGTGGTTATCGCTCTCGTACCCTGTGCTGTGGCTGCAAACACAAAGAAGGGAAAA 706

TATTTATTCAACTAATAGTCTTTTAATTTTTTTTAATCAAAGGAACAATATGAATTATACTGTGAGATGGGCTCCACATTCCAACTATGTAAAATATGTGCTGAAAATGATAAGGATGTAAAGATT 707

TTACATAGCTGAAAAAAGTCGCTGTTTAGATCCGTACCTGCCAGGATGTAAGACAGGATGTGCACATGAGGTGTCCACAGGGCTCAATCTTTACATCCTTATCATTTTCAGCACATATTTTACATA 708

TTACTATCTTTTGCTTCTTCTGCAGGAATCAGAAGGTCAGGGCTGTCCTTTCTGCCGATGTGAAATTAAAGGTACTGAACCCATCGTGGTAGATCCGTTTGATCCTAGAGGGAGTGGCAGCCTGTT 709

AATAAATGTGATTTGCCTTCTAGAACAGTAGACACAAAACAGGCTCAGGACTTAGCAAGAAGTTATGGAATTCCTTTTATTGAAACATCAGCAAAGACAAGACAGGTAAGTAACACTGAAATAAA 710

TGTGTTTCTCCCTTCTCAGGATTCCTACAGGAAGCAAGTAGTAATTGATGGAGAAACCTGTCTCTTGGATATTCTCGACACAGCAGGTCAAGAGGAGTACAGTGCAATGAGGGACCAGTACATGAG 711

CTGAATATAAACTTGTGGTAGTTGGAGCTGGTGGCGTAGGCAAGAGTGCCTTGACGATACAGCTAATTCAGAATCATTTTGTGGACGAATATGATCCAACAATAGAGGTAAATCTTGTTTTAATAT 712

GTGATGTTCCATGTAATACTGGACCAACTCAGCCAAAGTGGCAAATTTCTCCCCTCCATACAGGTCATAGTAATCACCAGTGTTCTGAATCTTGATGTGGGTGACAGCTCCATTTCTTCTAAAATA 713

TTTCTTTCCAGACACTACAACAACAGGAGTGCAAACTTCTCTACAGCCGAAAAGAGGGTCAAAGGCAAGAAAACAAAAACAAAAATAGATATAAAAACATCCTGCCCTGTAAGTATCAATAT 714

AAAACACTGTGAAAAGCAAAGCTTACCATGATGATATTTGCATTGATGTAATCTGAAACAGGCTCATTGGGATCACCATCGTGTAGGACAACCCTGGTATGATCAACTAGAAGAAAAAGAGACCAC 715

TGTCGCTTCTTGCCCACCAGATGACCCACCTTTCTCTCTGATGATGTCAATAAGAATATCAATCACAATGAACGTCCCTGTCCGGCCAATTCCAGCACTGCGGGCAGAAGGACAAAAAGCAG 716

TGACTGCGATATTGACGTTCCCAAAACCATCCAGATGGTGCGGTCTCAGAGGTCAGGGATGGTCCAGACAGAAGCACAGTACCGATTTATCTATATGGCGGTCCAGCATTATATTGAAACACTACA 717

ATAAGTAGGAAATAGCAGCCTCACATTGCCCCTGACAACATAGTTGGAATCACTCATGATATCTCGAGCCAATCCAAAGTCACATATCTTCACCACTTTCCCGTGGGTGACAAGCACGTTCCTGGC 718

TTACCTGACAGTGTGCACGCCCCCAGCAGGTTCACAATATTCTCGTGGCTTCCCAGCTGGGTCATCATCTTGAGTTCTGACATGAGTGCCTCTCTTTCAGAGCTGTCTGCTTTTTCTGTCAAAGA 719

TTTGCAGGGAAGGTACTAGGATCAGGTGCTTTTGGAAAAGTGATGAACGCAACAGCTTATGGAATTAGCAAAACAGGAGTCTCAATCCAGGTTGCCGTCAAAATGCTGAAAGGTACAGTATA 720

CTAAATTTTCTCTTGGAAACTCCCATTTGAGATCATATTCATATTCTCTGAAATCAACGTAGAAGTACTCATTATCTGAGGAGCCGGTCACCTGTACCATCTGTAGCTGGCTTTCATACCTAAATT 721

ACAGGTGACCGGCTCCTCAGATAATGAGTACTTCTACGTTGATTTCAGAGAATATGAATATGATCTCAAATGGGAGTTTCCAAGAGAAAATTTAGAGTTTGGTAAGAATGGAATGTGCCAAATGTT Til

TTTACCTTTGCTTTTACCTTTTTGTACTTGTGACAAATTAGCAGGGTTAAAACGACAATGAAGAGGAGACAAACACCAATTGTTGCATAGAATGAGATGTTGTCTTGGATGAAAGGGAAGGGGCCT 723

AATATCACAAGAACAACTGTTGTACCTGGAGAGTTTAAAAGGATCGTCTCACAAGATGTGCCAAGGGAATTGTATGCACAGCACTTGACCAGGAACCCTTTTATGGCTTCACTCATGTTTAGAGTA 724

ATGTTTAGAGTACTGCTCGACACCCACTGTCCAAACACTTTTCTGTTAGCCTTTCTATTCCAGACTCCTTCTGTGATCTCTTCTGTGCAGCTGAAAAAAAAAATAGCAAAGAATTTAGACAGGTGA 725

TTACTTGGGAGACTTGTCTGAACACTTCTTCCAGGTCCAAGATGGTAATGGGTATCCATCCGAGAAACAGGACGCCTGACTTGCCGATGCTTCTGCGAGCACTTGAGGTTTCCCTATAGAAAAGAA 726

AGCTCCAGTCGGGGGGTGCCCAGGTCAGTGGATCCCCTCTCCACCCTGGCCTACCTGGTCGCCATGGGCGTGCCTGCCAATGGTGATGGGCTTGGTCCAGCCAGGGACTAGGCGTGGGATGTTTTT 727

CCAGGGACTAGGCGTGGGATGTTTTTGCAGATGATGGGCTCCCGGAAGACAGTCCCCCCCAGGATGTTCCGGATAGTTCCATTGGGACTTTTCCACATCTTCTTCAGCTTGAACTCTGTGAGGACA 728

GGGAGGCTGTCAGTGGGGAACAAGAAGTGGAGAATGTCAGTCTGAGTCAGGCCCTTCTGTCTTGAACATGAGTTTTTTATGGCGGGAGGTAGACTGACCCTTTTTGGACTTCAGGTGGCTGTAGGA 729

TCTTTTAACTCAGGTACTGTGTATATACTTACTTCTCCCCCTCCTCTGTTGCTGCAGATCCGTGGGCGTGAGCGCTTCGAGATGTTCCGAGAGCTGAATGAGGCCTTGGAACTCAAGGATGCCCAG 730

CTCTTTCCTAGCACTGCCCAACAACACCAGCTCCTCTCCCCAGCCAAAGAAGAAACCACTGGATGGAGAATATTTCACCCTTCAGGTACTAAGTCTTGGGACCTCTTATCAAGTGGAAAGTTTCCA 731

CTCCCAGGACAGGCACAAACACGCACCTCAAAGCTGTTCCGTCCCAGTAGATTACCACTACTCAGGATAGGAAAAGAGAAGCAAGAGGCAGTAAGGAAATCAGGTCCTACCTGTCCCATTTAAAAA 732

CCTGTCCTGGGAGAGACCGGCGCACAGAGGAAGAGAATCTCCGCAAGAAAGGGGAGCCTCACCACGAGCTGCCCCCAGGGAGCACTAAGCGAGGTAAGCAAGCAGGACAAGAAGCGGTGGAGGAGA 733

SEQ scan_target_sequence ID

GCACAGCAGGCCAGTGTGCAGGGTGGCAAGTGGCTCCTGACCTGGAGTCTTCCAGTGTGATGATGGTGAGGATGGGCCTCCGGTTCATGCCGCCCATGCAGGAACTGTTACACATGTAGTT 734

CCTGCTTGCCACAGGTCTCCCCAAGGCGCACTGGCCTCATCTTGGGCCTGTGTTATCTCCTAGGTTGGCTCTGACTGTACCACCATCCACTACAACTACATGTGTAACAGTTCCTGCATGG 735

GGGCACCACCACACTATGTCGAAAAGTGTTTCTGTCATCCAAATACTCCACACGCAAATTTCCTTCCACTCGGATAAGATGCTGAGGAGGGGCCAGACCTAAGAGCAATCAGTGAGGAATCAGAGG 736

GAGTATTTGGATGACAGAAACACTTTTCGACATAGTGTGGTGGTGCCCTATGAGCCGCCTGAGGTCTGGTTTGCAACTGGGGTCTCTGGGAGGAGGGGTTAAGGGTGGTTGTCAGTGGCCCTCCAG 737

CACAACCTCCGTCATGTGCTGTGACTGCTTGTAGATGGCCATGGCGCGGACGCGGGTGCCGGGCGGGGGTGTGGAATCAACCCACAGCTGCACAGGGCAGGTCTTGGCCAGTTGGCAAAACATCTT 738

GTCACAGCACATGACGGAGGTTGTGAGGCGCTGCCCCCACCATGAGCGCTGCTCAGATAGCGATGGTGAGCAGCTG 739

TTCACTTGTGCCCTGACTTTCAACTCTGTCTCCTTCCTCTTCCTACAGTACTCCCCTGCCCTCAACAAGATGTTTTGCCAACTGGCCAAGACCTGCCCTGTGCAGCTGTGGGTTGA 740

GGATACGGCCAGGCATTGAAGTCTCATGGAAGCCAGCCCCTCAGGGCAACTGACCGTGCAAGTCACAGACTTGGCTGTCCCAGAATGCAAGAAGCCCAGACGGAAACCGTAGCTGCCCTGGTAGGT 741

GTCACAGACTTGGCTGTCCCAGAATGCAAGAAGCCCAGACGGAAACCGTAGCTGCCCTGGTAGGTTTTCTGGGAAGGGACAGAAGATGACAGGGGCCAGGAGGGGGCTGGTGCAGGGGCCGCCGGT 742

GCCGCCGGTGTAGGAGCTGCTGGTGCAGGGGCCACGGGGGGAGCAGCCTCTGGCATTCTGGGAGCTTCATCTGGACCTGGGTCTTCAGTGAACCATTGTTCAATATCGTCCGGGGACA 743

GGCTGGGGGGCTGAGGACCTGGTCCTCTGACTGCTCTTTTCACCCATCTACAGTCCCCCTTGCCGTCCCAAGCAATGGATGATTTGATGCTGTCCCCGGACGATATTGAACAATGGTTCACTGAAG 744

CTTGCAGCAGCCAGACTGCCTTCCGGGTCACTGCCATGGAGGAGCCGCAGTCAGATCCTAGCGTCGAGCCCCCTCTGAGTCAGGAAACATTTTCAGACCTATGGAAACTGTGAGTGGATCCATTGG 745

AGGTTTCAGCTGAGATAGCTCGAGAGAATGTCCAAGGTGTAGTCATACCCTCAAAAGATCCAGAACCACTTGAAGAAAATTGCGCTAAAGCCCTGACTTTAAGGATACATGATTCTTTGAATAATA 746

AAACCTCTAAAAAATTCTCTGAGAAGGCATTGCTACGAACCAGGGCAGGTATATGGTCCTTAGAATTCACCCTTGGCCATGGATCCTCCTCCAGTGACTGAAAAATAAGAAGGTAAAACAAATAAG 747

AAATGAAAGCCCAAGAAATTGAAAGAACCCCTCCAACAAACTTTAAAAGGACATTAGAAGAGTCCAATTCTGGCCCCCTGATGAAGAAGCATAGACGAAATGGCTTAAGTCGAAGTAGTGGTGCTC 748

TGGCCAGGAGTTGACATCTTCAAATTTTTTTGGTCCATGACAGTGTTTGTTGAATTAGTAGGCACAAGGCCAATTGGAAGGCTATTATTCAAAGAATCATGTATCCTTAAAGTCAGGGCTTTAGCG 749

CCAGAAGAAAATTGGAAATCCTTTACTTCATCAACACAGGAAAACTGTTTGTGTTTGCTGAAATGCATCTGGGAAATGAGGTTTTTCCAAACTTAGGATATAAGAGGGCTTTTTAAATTTGGTGCC 750 751

TCCGGGGGGCGGCCGTAGCGCGCCATTTGCACCCGC 752

GTCCCCTGTGAGCGAGTCCCACAGTGAGGAGACGATCCCCAGCGACAGCGGCATTGGGACAGACAACAACAGCACTTCTGACCAAGCGGAGAAGAGCTCAGAATCCCGAAGGAGGTACTCTTTTGA 753

GAGGAGGAGGAGGCAGAGGACAAGGAGGATGATGAGGACAAAGATGAGGATGAGGAGGATGAGGAGGACAAGGAGGAAGATGAGGAGGAAGATGTCCCCGGCCAGGCCAAGGACGAGCTGTAGAGA 754

GTCCTCTGCCTCCTCCTCCTCTTTGCGTTTCTTGTCTTCTTCCTCCTCCTTAAGCCTCTGCTCCTCGTCCTGTTTGTCCTTCATTTGTTTCTCTGCTGCCTGCAGGCAGAGCACACACCTCAGGGC 755

ACCAGTGACAATGACCGCCTGCGCAAGCGGGTGGAACAGCTGAGCCGCGAACTGGACACGCTGCGGGGCATCTTCCGCCAGCTGCCAGAGAGCTCCTTGGTCAAGGCCATGG 756

CAAGAACAGCAACGAGTACCGGGTGCGGCGCGAGCGCAACAACATCGCGGTGCGCAAGAGCCGCGACAAGGCCAAGCAGCGCAACGTGGAGACGCAGCAGAAGGTGCTGGAGCTGACCAGTGACAA 757

GTGCGAGGGCGGCGGCGGCGGCGGCGGCTGGTAAGGGAAGAGGCCGGCCAGCGCCAGCTGCTTGGCTTCATCCTCCTC 758

GGCCCCACGGGCGGCGGCGGCGGCGGCGACTTTGACTACCCGGGCGCGCCCGCGGGCCCCGGCGGCGCCG 759

TGCCGGCTGTGCTGGAACAGGTCGGCCAGGAACTCGTCGTTGAAGGCGGCCGGGTCGATGTAGGC 760

GCGCGGGGCCCGCGCCCCGGGGAAAGCCGAAGGCGGCGCTGCTGGGCGCGTGCGGGGGGCTCT 761

ATTTTGATTTGCAGGCTGGGTTTGACCAAAGAAGAGTCATTGCAGCAGAACGTGGGCCAGGAGGAGGCTGAAATCAAAAGTGGCTTGTGTGTCCCAGGAGAATCAGTGCGTATACAGCGTGGTCCA 762

AAGGAATCTGTACAAAAAACAGGAGTCAGAACAAGCAGGGGTTGCTAAGGATGCAAAATCTGTGGCCTCAGATGTTCCCCTCTACAAGGATGGGGAGGCTAAGACTGACCCAGCAGGGCTGAGCAG 763

TGTTCTGACTCCTGTTTTTTGTACAGATTCCTTCTGGCTCTGGTTCGGAGATCTGGCCGAGAGCGTTTCTTAAAATGCCCATCTCGCTGTCGGGTGGCTGGACCACGCTGTATACGCACTGATTCT 764

GTGGCTTCTCGGATCCAGGCTGAGCCAGACAACTTGGCACGTGCCTCTGCATCTCCAGACAGAATTCCTAGCCTGCCTCAGGAAACTGTGGATCAGGAACCCAAGGATCAGAAGAGGAAATCCTTT 765

ATGCAGAGGCACGTGCCAAGTTGTCTGGCTCAGCCTGGATCCGAGAAGCCACAGACTCAACTGGGAATTCGGGACCCTCCAGGTCGGGTGCTGCAGAGGATGTGCCTGGCAGATGGGGACTGCTCA 766

AACCCAAGGATCAGAAGAGGAAATCCTTTGAGCAGGCGGCCTCTGCATCCTTTCCCGAAAAGAAGCCCCGGCTTGAAGATCGTCAGTCCTTTCGTAACACAATTGAAAGTGTTCACACCGAAAAGC 767

TAAAACTATTTTCTAATTCTTTTTTTGCAGATTCAACTTTCACGTATCAAACCACCCTGGGTGGTTAAAGGTCAGCCCACTTACCAGATATGCCCCCGGATCATCCCCACCACGGAGTCCTCCTGC 768

CCACTGCCATAGAGAGGCGGCCACCACTGCCATCGGAGGGGGGGGTGGCCCGGGTGGAGGTGGCGGCGGGGCCACCGATGAGGGAGGTGGCAGAGGCAGCAGCA 769

CCTCTCTATGGCAGTGGTGACCTCTCGCCCCTCGGACCTGCAGAGCACGGGCTTTAATGTCTGCGAGGGTCCTGGCGCCAGTCCAACCCCGGCAGGAGGACTCCGT 770

AGGAGAGAGGACCTGCCTTCTCTGAGAAAGGAGGAAAGCTGCCTACTACAGAGGGCTACAGTTGGACTCACAGATGGGCTAGGAGATGCCTCCCAACTCCCCGTTGCTCCCACTGGGGACCAGCCA 771

CAGCTTTCCTCCTTTCTCAGAGAAGGCAGGTCCTCTCTCCTAGCTCTGGACATGGCAGTTCCGGCCTGGGTATGCTCCCCATTTAGAGGATAAGGCGGCAGTAGTTGTGTTCGCTGTAGATCTGAC 772

GGAAAGTGATGATGAGGAGCAAGGACCCACCGTTCCTGCAGACAATGGTCCCATTCTGTCTCTAGTGGGAGATGATACATTAGAGAAAGGAACTGGCCAAGCTCTTGACAGTCATCCCACTATGAA 773

GTCCTTGCTCCTCATCATCACTTTCCCAGGAAGTGGTGCCAGACTCACATTCAGTTCTAACATCCGGATGCAACTGAGGCTGCTCCACTAATCTCTCAGCTACTGAGGTTTGGGAGGACAGTAGGG 774

SEQ scan_target_sequence ID

CGAATTAGGGCTTGGTGGCTCATGCCCTCCTATGAGGGAAAGTGATACTAGACAAGAAAACTTGAAAACCAAGGCTCTCGTTTCTAACAGTTCTTTGCATTGGATACCCATCCCATCGAATGATGA 775

CATGAGCCACCAAGCCCTAATTCGTCATCAAATGCTCTGTTCTGCAGGCAATCAGTCGGTGAGGATTCAGGTGTGGAACTGGGGGTCACATTTACAGGATCCTTCATAGTGGGATGACTGTCAAGA 776

ACAGCTGAGGAGGGTCTAGATCCTCTTGACAGCCTTACTTCACTCTGGACTGTGCCATCTCGAGGAGGCAGTGACAGCAATGGCAGTTACTGTCAACAGGTGGACATTGAAAAGCTGAAAATCAAC 777

TGTCAAATCCCCAGGCAATGCAGGAGGGGTGGGAGCAGCTTTCTCCCACTCCTCTCCAACCTGGGGCTCAACAGATGGTATGTGTTCTCTGGATTCTGGTTTGGGCTGTTTCACTACCTCATCATT 778

TAGTGTCAGCCTCACTGCTGTCCTCCGTGAGGTGACCTTCAAAGTCAGAGGCTGTATCCGTGGACTCACCGTGAGGACTCAGTGCTTCAGAGTCTCCGTTGATTTTCAGCTTTTCAATGTCCACCT 779

GCATGTCACCATTCACCTTGGACAGTGGGGCAGATTGGTTCCAATTGGGTTTCTCATCCTTGTCCACCGAAGATCCCTTTGTCACTGCAGCTTCTCTAGTGTCAGCCTCACTGCTGTCCTCCGTGA 780

TCCGCCAAAAGATCCCAGATTCCCTACTGCTGGCCAGTACTGAGTACCAGCCAAGAGCCGTGTGCCTGTCCATGCCTGGGTCCTCAGTGGAGGCCACTAACCCACTTGTGATGCAGTTGCTGCAGG 781

TACTGGCCAGCAGTAGGGAATCTGGGATCTTTTGGCGGACCGCACATACTCGAGACACCCAGCTCTGAGGAGCAACCATCCCATCTGTCCTTGTAACCAGACGCATGTCACCATTCACCTTGGACA 782

CATGTAAAGATCCCATGCGTAGCGAGCCATGGCTCTGGTCTTTTGTAAGTGGTACTTGTGGGGATTCTGACATGCTGTCATCGTGGGCTGGTGGAAGAACCTTCTCTAGGGGCAAGCTACCCTGCA 783

TAAGGGCTTTGAAGGAGCCTCTTCTGCCAGATAGCTGTGAAACAGGCACTGGTCTTGCCAGGATTGAGGCCACCCAGGCTCCTGGAGCACCCCAAAAGAATTGCAAGGCAGTCCCAAGTTTTGACT 784

TGAGGCCACCCAGGCTCCTGGAGCACCCCAAAAGAATTGCAAGGCAGTCCCAAGTTTTGACTCCCTCCATCCAGTGACAAATCCCATTACATCCTCTAGGAAACTGGAAGAAATGGATTCCAAAGA 785

CAAGACCAGTGCCTGTTTCACAGCTATCTGGCAGAAGAGGCTCCTTCAAAGCCCTTAAAGAACTGGGGCTGCTTCCATCAACCATGCCACTGTTTTTTCCAAGACCATGTAAAGATCCCATGCGTA 786

GATTCCAAAGAGCAGTTCTCTTCCTTTAGTTGTGAAGATCAGAAGGAAGTCCGTGCTATGTCACAGGACAGTAATTCAAATGCTGCTCCAGGAAAGAGCCCAGGAGATCTTACTACCTCGAGAACA 787

AACACCTCGTTTCTCATCTCCAAATGTGATCTCCTTTGGTCCAGAGCAGACAGGTCGGGCCCTGGGTGATCAGAGCAATGTTACAGGCCAAGGGAAGAAGCTTTTTGGCTCTGGGAATGTGGCTGC 788

TTGGCTCTGGGAATGTGGCTGCAACCCTTCAGCGCCCCAGGCCTGCGGACCCGATGCCTCTTCCTGCTGAGATCCCTCCAGTTTTTCCCAGTGGGAAGTTGGGACCAAGCACAAACTCCATGTCTG 789

CCAAGCACAAACTCCATGTCTGGTGGGGTACAGACTCCAAGGGAAGACTGGGCTCCAAAGCCACATGCCTTTGTTGGCAGCGTCAAGAATGAGAAGACTTTTGTGGGGGGTCCTCTTAAGGCAAAT 790

TCCTCTTAAGGCAAATGCCGAGAACAGGAAAGCTACTGGGCATAGTCCCCTGGAACTGGTGGGTCACTTGGAAGGGATGCCCTTTGTCATGGACTTGCCCTTCTGGAAATTACCCCGAGAGCCAGG 791 iAGAGCCAGGGAAGGGGCTCAGTGAGCCTCTGGAGCCTTCTTCTCTCCCCTCCCAACTCAGCATCAAGCAGGCATTTTATGGGAAGCTTTCTAAACTCCAACTGAGTTCCACCAGCTTTAATTATT 792

TTAATTATTCCTCTAGCTCTCCCACCTTTCCCAAAGGCCTTGCTGGAAGTGTGGTGCAGCTGAGCCACAAAGCAAACTTTGGTGCGAGCCACAGTGCATCACTTTCCTTGCAAATGTTCACTGACA 793

GCAAATGTTCACTGACAGCAGCACGGTGGAAAGCATCTCGCTCCAGTGTGCGTGCAGCCTGAAAGCCATGATCATGTGCCAAGGCTGCGGTGCGTTCTGTCACGATGACTGTATTGGACCCTCAAA 794

GTTATATAAAAAGGTAACAGTTGGCTTACTGGAAGTTGACTTTGTCCACCTGGAACTTGGTCTCAAAGATTCCAGAAGTCAGGACACGGCAGCGAAGCAGGTCCTGAAACAAAATT 795

AGCAGCGCGGAGCCGGTGGAGGCGTTGGTGCAGGGCGGCAGGATGCGCGGCGGCGAGCGCTCGCCGCCCACCATGGAGAACTGGTAGGAGCCGGCCGAGGCGCCGTAGTACA 796

CCGGCCGAGGCGCCGTAGTACAGGTGGTAGGAGGGCGAGCTGGCTTGGAACGGGCCTCCCTGCGCTTGCGACGAGCCGGGGTAGG 797

GCGGCGGCAGGTAGGTGTGGTAGCGCGTGGCCGAGCCCATGGCCGACATGCCGATGCCGATGCCCGA 798

TGTGGTAGCGCGTGGCCGAGCCCATGGCCGACATGCCGATGCCGATGCCCGAGGTGACCGGCGTCGGGGAGTAGGTGAAGGCGCCTGGATAGTGCAT 799

CGCCTGGATAGTGCATGCGGGGGTCGGAGATGGAGGGCAGCGCGGGGAACTGGCGCGGGTCGCTGAACGCTGTCAGGTCGGGTGCCGCTGCAGGGCGGGCAAGAGAACGGA 800

CACCCAGCAACGCCCATTTCACCTGGACGTGCCAGCGGCATGACAACCCTCTCTGCAGAACTTTCCAGTCGACTCTCAAGTAAGCCACTTGAAAACACATTCTTTGCAGCTGAGCTGGGGTGGAAG 801

TTTACATATAATTGACCTTTCTGATTCTCTTCAGATACAAGGCAGATCCAACCATCCCCACCGTGGTCCTACGATCAGTCCTACCAATACCTGGGATCCATTGCCTCTCCTTCTGTGCACCCAGCA 802

CCAGTTGTGGGTGGTGGCCCAGGTGCAGGAGAGGCGGGCAGTGGGCTCCATCTGGTACTTACCCTGCATCTGACTCTGAGGCTGAGGGTTAAAGGCAGTGGAGTGGTTCAGG 803

TTCAGGGAGGCACGAGGGTTGGGCGTGGGGGCTGGGTGGTGTGGGCTGACCCTCATGGCTGTGCGCCGCAGCTGCTCCAGTTCACTGAGCCGCTCGGAAAAGGACAAGCTCC 804

CCCATCCCCTCCCCTCCCTGCTCCCCACAATAGGACATCGGCAGAAACTAGATGATCAGACCAAGCCCGGGAGCTTGTCCTTTTCCGAGCGGCTCAGTGAACTGGAGCAGCT 805

ACAGGGAAAAGCTTCACTCTGACCATCACTGTCTTCACAAACCCACCGCAAGTCGCCACCTACCACAGAGCCATCAAAATCACAGTGGATGGGCCCCGAGAACCTCGAAGTAAGTGCATCCACTTG 806

TTTCAAGCATAGTTTTGACAGATAACGTACCTCTTCCACTTCGACCGACAAACCTGAGGTCATTAAATCTTGCAACCTGGTTCTTCATGGCTGCGGTAGCATTTCTCAGCTCAGCCGAGTAGTTTT 807

AAGTGTATGTATAACATCCCTGATGTCTGCATTTGTCCTTTGACTGGTGTTTAGGTGGTGGCCCTAGGGGATGTTCCAGATGGCACTCTGGTCACTGTGATGGCTGGCAATGATGAAAACTACTCG 808

CTCTCCGGGCCAGTACCTTGAAAGCGATGGGCAGGGTCTTGTTGCAGCGCCAGTGCGTAGGCAGCACGGA 809

TAGGCAGCACGGAGCAGAGGAAGTTGGGGCTGTCGGTGCGCACCAGCTCGCCCGGGTGGTC 810

AAAAGGCTGTGATTGACTTGAATAACCGTTGGTTTAATGGACAGCCGATCCACGCCGAGCTGTCACCCGTGACGGACTTCAGAGAAGCCTGCTGCCGTCAGTATGAGATGGGGTGAGTGAGGAGTG 811

TCGGTTTATTGTGCAACCGAGAGCACCTGTCTCCATGACGACATGCTCCAATTTTGAAATAAAATGAACAGTTGACTCTGTAAGGGAAAATGAGAGCTGATTATTTTGCTGGGAAGATATCAAACA 812

ATGACTATGACCCTGACGCAAGCCTGGAGTACAGCGAGGAAGAAACCTACCAACAGTTCCTAGACTTCTATGAGGATGTGTTGCCCGAGTTCAAGAACGTGGGGAAAGTGATTCAGTTCAAGGTGG 813

CATCCCTCCTGCACTGCTCCATTCCAAACGTCGTAAACATGCTCTTAATAAGAAGGGTAGGACTGGATGTTGGGAAATTATGTTTACGTGAACATCTGCGTATGAAAGAAAAGCTTAAATTCACTA 814

TGTGACAAATCAGGAAGACATCCACAAGCAGAATACTTACGACTGGTACTGAACATATACATTGCCCCTCAGGTGAGGTTCCAAATTGCAGCTGACCTAGGGAGCAATGAAGAATGCTATCATAAA 815

SEQ scan_target_sequence ID

AAAGGGAAGAAGAATGCCAAGCAGCCCTTTCTCTGTTTAACGGACGATGGTATGCAGGACGACAGCTGCAGTGTGAATTCTGCCCCGTGACCCGGTGGAAAATGGCGATTTGTGGTAAAAGACAAAGTGATGATTTT 816

GCTCACCAGTAGTTGTCTGAGGCCAGATCACTGGGGTGGAGCCACTCTACAGAGGAGCCCAGCAGAGTCTGAATTTCGTTCGTGAATTCCACCAGATCTAACAGCTCCTTACTTTCAGGGTTGAAG 817

AATTTCCACGTTTGGAAAATTGCAGCGAAATATGCGGGAGGACATTTTCAATTTCTTAAGGACATCCGAAAGCAGTAGCCAGTTTCGTGGCCTACAAAACAGAAAGGAAAATGCTTTGAGTTTCCA 818

GCATATTTCGCTGCAATTTTCCAAACGTGGAAATTGTCACCATTGCAGAGGCAGAATTTTATCGGCAGGTTTCTGCAAGTCTCTTGTTCTCTTGCTCCAAAGACCTGGAAGCCTTCAACCCTGAAA 819

TCATACCTGTTAAGAACTTTTCCATAAGTTCACTGTGGGTCATTTTCATGATGGTTCTACCTGAGTACGTAGCCAAGGTGGGGTCAGCACCATAAGAGAGAAGTAGTCGGACAATTTCCAAGTGAT 820

AAAGGAGACAACTGCTTTATAAGCAAGTGTGGCTTGCATGAGCATAATTCTATTGCGCCTCTCTTCCTAGGCCTCTGCACGATGCTGTTGAGAACGATCACTTGGAAATTGTCCGACTACTTCTCT 821

CATTGGCATTGGGGGCGGGTGATGCGGAGGCTGGGCGGCCTGCACTCGACACTGACCCTGAAACGTTAGTGATGACAGCATCGGTGCCGCCCATGCGCGGGCATGATGAACTCCGCTGCTGTGGTA 822

TTCAGATCTATAGATAGCACAACCATTTCCTGGAGGAGATAGTGTTTCTTTCGGAATCTCACTTCCGGAGAGCACTAAGCCACTTCCAGCCCTGCTGTGAACCAGGACCGTGGGAGCCATCTTTTT 823

ATCTATAGATCTGAAATCATCAGCACTGCTCCCTCATCCTGGGTGGTGCCCGGGCCAAGTCCTAACGAAGAGAACAATGGCAAAAGCATGTCGCTGAAAAACAAGGCATTGGACTGGGCGATACCA 824

CCCCTTCTGTCCTCGCAGGTTAATCCCCAGAGGCTCCATGGAGTTCCCTGGCCTGGGGTCCCTGGGGACCTCAGAGCCCCTCCCCCAGTTTGTGGATCCTGCTCTGGTGTCCTCCACACCAGAAT 825

AGGCCTACAGACACTCCCCAGGTAACTCCATTGAGTGGCTGTCTTGGCATTGGCTGAGTGCTGTTGGGGTTGCCATGGAGATCCTTGGCTAGGTCAGAATACCACTGTGAGGATATCTCAGAAATG 826

CTGTAGGCCTCAGCGTCCCTGTAGTAGGCCAGTGCCGCAGCTGCAGCGGTGGCTGTGCTCGGGGCAGTGGAGGAAGCTGCTGCATCCAAGCCCTCAGGCCCAGAGGGGAAGAAAACCCCTGATTCT 827

AACAGGGCTGAAGGCCAGGCCCCACCTGCAGATTCAGGGCTAGATGTCGTGTCTTGGTCTGTTCTAGGTCACTCTGGGAGTACTTGAGCCGCATCTGCAGTCCATGGGCCTGAGACTGCACCTGAC 828

ACTGCACCTGACGCAGCTCTGCCTCTTTCCGTTTTGCCTTCATCTGCTCCTGAAGGGAACAAGAAAGAAGGGCTAGGTGGTAAGGTGGTGGCTGACCTAGGCTTAGGACTCCCACTGCTAAAAACA 829

ACCTAGGCTTAGGACTCCCACTGCTAAAAACAGCACTGCCTGTGGCTTACTTTCAGCTCCTCTGTCAAGCGCTCCTTCTTCTCTTTCAACTTGTCTACTGCTTTCTCATCCCAGCGCCGTGCCTTG 830

GGCCTTCAGGTCACTGGCCCCACCAGAGATCACTCCTGACTTCTGGAATAGGGTTCCATCCAGTGCCACTGTCTACACACAGCAGGGGGAAGAGAGAAGAGGGGGAGAAGCTGAACAAATGAATCT 831

GAGAAGCTGAACAAATGAATCTCCAGTACTGAGCCTGTCCAGCTCCAGCCTGGGCAAGGGAATCCACACCTTGTGGCGCTGGTGGCCTCCAAAGGCAATGCGGCGGGCATCTTCCACGTTGTCACA 832

CAGCTCCCGGAGTTTCTCATCTGTAGGCTTCACCTGTGGGGAGAAGCTCAGTCAGTGGCAGAACACAAACAGGGAGTACTAGAGGAGGGGCCCTTGAACACTGGCCTGACCCAATCCCCAACAAG 833

AACTCCGGGAGCTGAAGGGGGCCAAGCTAGTGATTGATGTGATTCGCTATGAGCCACCTCATATCAAAAAGGCCCTGCAGTATGCTTGTGGCAATGCCCTTGTCTGTGACAACGTGGAAGATGCCC 834

TAATGGCATCCATGTTCTTGCCCAAAACCTTGGTTACAGCAATCTGATACTTCTTTTGTGTGGGCTGGCATAGGTCAATGAGGCGGCCGTACTGAGTAAAGTAGGAAGGGAAAACTGAAGTATGAA 835

TGGATGCCATTATTGTGGACTCGGAGAAGACAGGCCGGGACTGTATTCAGTATATCAAGGAGCAGCGTGGGGAGCCTGAGACCTTCTTGCCTCTTGACTACCTGGAGGTGAGGCTTGTTGGGGATT 836

AATATGGATAATACACAAAGACAATATGAAGCAGAACGGAATAAAATGATTGGAAAACGAGCCAATGAGAGGCTAGAACTCCTGCTACAAAAGCGGAAAGAGGTAAACTTTTATATTGAATATTTA 837

CCAATCATTTTATTCCGTTCTGCTTCATATTGTCTTTGTGTATTATCCATATTAATGCTAAGATTTAGTGCCACATTCACCAAAGCTGTCATCAACTTCATAGCTATTTTTAAAGAGTAAAAGTAT 838

AGCTTCAGGAAAATCAAGATGAAATAGAAAATATGATGAATGCAATATTTAAAGGAGTGTTTGTACATAGATACCGGTAAGTTGTGACAGTTTTTTTCATAAATAGCATTATGTAATTTCTACTCA 839

CCCATTCAGTGATGCGATAGCTGAAATTCGAGCTATTTGCATTGAAGAGATTGGCATTTGGATGAAGATGTATAGTGATGCCTTTCTTAATGACAGTTATTTAAAATATGTTGGTTGGACTATGCATGATAAGGT 840

TTTTAATGCATTGTCTCATCTTTTTTTTTTTTTTTTTTTAGCAAGGTGAAGTAAGACTCAAATGTCTTACTGCTCTACAAGGGCTTTATTATAACAAAGAGCTTAATTCCAAACTGGAACTTTTTA 841

ACTTTTTACCAGTCGGTTCAAGGTTAGTATTACTTAAGAATTTACAAATAACTTGTCATTTGCAAACACTTTTCTCTTGCTTTCCTTTTAAAAATATTTTAATTTTTTTGTCCTTAGGATAGAATT 842

TAAAAATATTTTAATTTTTTTGTCCTTAGGATAGAATTGTGTCTATGACCCTTGACAAAGAATATGATGTTGCAGTACAAGCAATAAAATTACTCACTCTTGTTTTACAGTAAGTATGTATTTGTT 843

ATATATAGATTTACTTTTTGTAGAGAAATTCTCCAGCTGCTACTGCTACTGGCCGGTGAGCTGAATAAACCAGATGATAGACATTTTCACAATCTTCTGCAGTGAGAACTTCTTCACTACTCCTAA 844

GATTTCTTTTCAAGGTATGTTTACTTGGAAAAGTTCATGACCTTTCAGATGTCACTCCGAAGAGAGGATGTGTGGCTTCCACTGATGTCTTACCGAAATTCTTTGCTAGCTGGTGGTGATGATGAC 845

TTACTGAGTGAAAGCTGCATGCCCTCAACCACTTTCCGTTTTCCTGTAGATGGTTTTGATTTTTTACTCCGTACTGTTGACCCCCGGCTGCTGATTCCACTAATGACTGACATGGTGTCATCATCA 846

AAAAAAGGGCCTACAAGACAGCGCAAATGTGGCTTTTGTAAGTCAAATAGAGACAAGGAATGTGGACAGTTACTAATATCTGAAAACCAGAAGGTGGCAGCGCACCATAAGTGCATGGTAAGTATA 847

CAGATATTAGTAACTGTCCACATTCCTTGTCTCTATTTGACTTACAAAAGCCACATTTGCGCTGTCTTGTAGGCCCTTTTTTCTGTTCAACTGAGCTTGACATGATTTTTAAATTGCCTTTAGAAT 848

ATAAAGCTCAAATACGAGAGAAACCTTCACAAGGAATTTACATGTAATTATTTAACTTCTCTTTAAGTTTTTTTTTTAACAATAATACTTTCTTTGGGCTTTTGTAAAAATTTTTCCCATTTCAAA 849

TTTATCATGCAATGCACAGTGGTAGTGGTATGTCCTGTGACATGTTTTCACATCACAACCAATTGTTGCTCCAGGACAATGGCACAAAGAACACATCTACAGCAAAACGACAAAATAATATTATTA 850

ATTTCTTCATTTTTTATAGGGTCTATTGCCGAAAACACAAGAAAACTGCACATAACTCCGAAGGTACATCATTTAG 851

AATACCGATAGCATATTTTCATGATTTTTTTTAAGTTCGTTTTTTCTTTTACATTTGCAGAGAGATAGGTCTCCACACAGAAGCAGCCCTAGTGACACCAGGCCTAAATGTGGATTTTGCCATGTA 852

TTGGGCTTAAAAGAACCATGCTTACCATGCACTTATAATGGGCAGCTGCCTTCTTGGCATTAAATATATGCAGTTTTCCTCGTGCTTCATTTTCTTCCTCCCCTACATGGCAAAATCCACATTTAG 853

GACCATTCTTTTTCCTCGTTTAATCTCCTGAAGTACAGTTTTAATATCAAAGTCTCCAAATTCTGCTCTTGATGTTGTTGTGAGCTGGACTGTGCCAGAAGAAAACAACTAGAGAAGAAAA 854

TGTTTTCTTACTTGTAAATTCCTCGTGACATATTTTCAATGTATTTAGCTTTGTCTTGTACTCCACAGTGGTAATGGTAAGTCTTAACACAGGCTTTTATTTCACATCCAATAGTAGCACCAGGCT 855

SEQ feature_start feature_stop probe_ failure mip_sequence ID _position _position strand -flags TCAGACTTCGGCCCACCCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTGGTCCACCGCCAGTCTCCTGCCTGG 856 43814931 43815035 - 0 GTGTGGAGGGTAAGGGGGCAGGGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGATGGCAAATACACAGAGGAA 857 115256486 115256577 + 0 GTAGCCCGCTGACCTGATCCTGTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCAACAGGTTCTTGCTGGTGTG 858 115258743 115258748 - 0 ACTGGGAAACCAAATACCCTGGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTACCTCAGTTTGCCCCCATGTC 859 25457148 25457289 + 0 GCTGAAGGAGTATTTTGCGTGTGTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTCACCCTGCCCTCTCTGCCT 860 25457144 25457294 - 0 CCCGGGTTGTGCTGGCATCTGGCTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTCCTCTTTTCTCCTCTTCAT 861 25458573 25458698 - 0 GCAGGGAGAAGGAAGGGCAGGATNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGTTATCCAGGTTTCTGTTGTT 862 25459792 25459882 - 0 GCTCCTGGGCCTGGGGGGCTGTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGCTGTTTCATGCTCCTCCTTGG 863 25461992 25462092 - 0 GCGCATCATGCAGGAGGCGGTAGANNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNAGGTAGAAGCCATTAGTGAG 864 25463166 25463483 + 0 GCGTTAGTGACAAGAGGGACATCTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGCCCCAGCTGATGGCTTTCT 865 25463166 25463483 - 0 GCTGTCCAGGGACAGAGGCAGACANNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGTGGAGGGGACAGGATGGTA 866 25463503 25463605 + 0 TTGGAGCCATCTCCCTGGCACCCTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTCCTCACACACCTCCGAGGC 867 25464533 25464580 + 0 GTCCATGCTGTGGGGCGCAGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGCTGAAGGACTTGGGCATTCAGGT 868 25464429 25464508 - 0 GTGAGGGGTGCAGGCCCAAGAGGTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGCTGGGTGGGAGCTTGGGAC 869 25466760 25466845 - 0 CTTCCTTAATGGCTGCCTGGGCAGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCCCAGCACTCACAAATTCCT 870 25467088 25467139 + 0 GCCTGGGGCGCGGTCTCGAGCTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNAAGGGTACCTACGGGCTGCTGC 871 25467018 25467212 - 0

CCCTGGAACTGCTACATGTGCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGTCTCCTCTGCTCACTGGGTCT 872 25467018 25467212 - 0 GCTGTTGTGGCCTCCAGTGGTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGTGGTTTCTGACCCTTCCCGCTG 873 25467407 25467525 - 0 GGTGAGTACCACCGAAGGGCCTCTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTCCTGGGTGGGTGTGCTCCT 874 25468119 25468204 + 0 TGCCGTTGAGGCCGGCCCTTCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCATCCCCTCCCTCTGCTTTCCAG 875 25468119 25468204 - 0 CCGCGCCTGCTCCTCGGATGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCTTCCTAAGTGCCTCTGCTACTCT 876 25468879 25468940 + 0 CACATGTCCGTGTACACTTCTTTGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTCCTGGTGCCACCCTCTCCA 877 25469025 25469183 + 0 TTCCCCCACCCTCCTTACAGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGGGCTTTTTGGCTGGTGGAGGTGG 878 25469025 25469183 + 0 GTGACACGCCAGGGTTGGGGTTGTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTAGGGCCAGAAGGCTGGAAG 879 25469487 25469650 + 0 GGCTGCCAAGGCCTCCACAGAGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTGATTGAATGGGCCCTGGGGGG 880 25469487 25469650 - 0 CACCCACCCCATGCCTTGCAANNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGACCTCGTAGATGGCTTTGCGGT 881 25469917 25470030 + 0 GCACTAGGAGGCCTGGAAGTTGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGGTGTGTGTTGAGAAGCTGATG 882 25469917 25470030 - 0 TTCCCCCACACCAGCTCCCCAANNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCTACTGCCAAACCCCACAACTT 883 25470458 25470621 + 0 GTGTCTTGGTGGATGACGGGCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNATGGGGGGATCAGGGTGGCAGGG 884 25470458 25470621 - 0 CGGGCCCCTGGTTTTCTTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTCTGGCTCGTCATCGCCTGCTTTGGT 885 25470974 25471055 + 0 AGGTAATTGGTGGATTTACCTTTCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGTAGTTGGCATATTCTGCAT 886 198266442 198266624 + 0 CTGGATATGTTTCATGGTTCTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTGGGTATCTTATTCCTCTTATGG 887 198266442 198266624 - 0 GTGTTAAAGCCTTTATGGAAGGGTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTAGGTAATGTTGGGGCATAG 888 198266810 198266849 - 0 GAAAGGACAGTCATGAGTTGGTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGGGCAATAAAGAAGGAATGCCC 889 198267481 198267491 + 0 CTTATGGGCTGTGCCATCTTGCCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCGTAACACAACAGCTAGAGCT 890 198267342 198267373 - 0 GGTGCCATTTGGTGATTTCCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCAAAATCACATTATTGCCAACATG 891 209113112 209113210 + 0 TGCAGGAGAAGTCATCCCCCTTCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTCTGAAAACTGGTGGTTGCCT 892 128200060 128200163 - 0 GGTGCCGGCTCTTCTGGCGGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCATTGTGCAGCTTGTAGTAGAGGC 893 128200661 128200789 + 0 CACTCATCAAGCCCAAGCGAAGACNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTGTCTCTCCCTGTTCCCCTG 894 128202700 128202851 - 0 GTCCAGGAACTGAGCAGAGGTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGTTGCTGAGGTTTTCCAGCACTC 895 55589745 55589869 + 0

SEQ feature_start feature_stop probe_ failure mip_sequence ID _position _position strand -flags

GTGAATACACTATTAGGTTGGAGGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGCAGGACTGTCAAGCAGAGA 896 55599285 55599349 - 0

GCCCACTGCCTGAGAGAGCTCATNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNACCAACCATGTTGAGGGCAAC 897 106155099 106155185 + 0

GTAGAGGGTATTCCAAGTGTTTGCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNAAATGGAGACACCAAGTGGC 898 106155144 106155319 + 0

GTTCTGTCTGGCAAATGGGAGGTGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTGGCTTCCCTTCATACAGGG 899 106155144 106155319 - 0

TCTGTAGCCCAAGAAAATGCAGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCTCTGGGCTCCTTCAGATCAAG 900 106155044 106158550 + 0

CGACTATTCTGGCTTCCCTTCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGTCTTTCTCCATTAGCCTTTTGG 901 106155044 106158550 - 0

TGGAACACACACATGGTGAACTCCTGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCCAGAGCTTCAGATTCTG 902 106155646 106155733 + 0

CATTTGGTTGACTGCTTTCACCTGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNACTTTTCCCCTCCTGCTCAT 903 106155044 106158550 - 0

GTGAGTGAGGCCTGTGATGCTGATNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNAGAAAACCACATCTCACATA 904 106155044 106158550 + 0

GCACCATTAGGCATTAGCACTGCCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNACTCATTAGTAGCCTGACTG 905 106155044 106158550 - 0

CCAGCAGCAATTTGCAAGCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTACCTGTTCCTTTCAGAAACCAGAA 906 106156091 106156165 + 0

GCAGCTGGCTTTGGAGGCAGCTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGTTATTTTCTGCAGGAGATGGG 907 106155044 106158550 - 0

CACCACCACTACCCCAACCAAANNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCTCAGTGTTCACTAAGGATTCC 908 106155044 106158550 + 0

TGAACAGAATTCTTCACCANNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGCAATTGTGATGGTGGTGGTGGTGT 909 106156165 106156274 - 0

CCAATGTCAGAACACCTCAAGCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNACCACCTTCCCAGAGTCCTAAT 910 106155044 106158550 + 0

GCTTTTTCCTTCTGAAGGAAGCTGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGAAGGGCTGCATACATGTGT 911 106155044 106158550 - 0

CGTAATGAGGCATCACTGCCATCANNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTGATGAGAAACAAAGAGCAA 912 106155044 106158550 + 0

.CACAATGGAACAGTCATTGTCCCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCGTGTTTGCTCCTTGTCTCG 913 106155044 106158550 - 0

CCCTCACACCAGGTGCACTTCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCTGGAAATTCCAACATGCCTGGG 914 106155044 106158550 + 0

GGGATTCCGCTTGGTGAAAACGANNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGCTGTGTTGTTTTCTGGGTGT 915 106155044 106158550 - 0

TCCCAGAGTTCACATCTCCCTCANNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCAACAAAGAGCAGATTCCCAA 916 106155044 106158550 + 0

GGAACTGGAGATGTTGGTCCACTGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGTGCTGTTTCAACACTGGGG 917 106155044 106158550 - 0

GAAATTCCCCTTATAGTCAGACCATGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNATGATCAGCAAAGAGAAG 918 106157293 106157510 + 0

GGTTGTGTTTGTGCTGCCTGTTTATGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTTAGTCTGGCCAAAGAAT 919 106157294 106157418 - 0

GCTTTCAAGAACAGGAGCAGAAGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCTTGTTCAAACAATACACACC 920 106155044 106158550 + 0

GACATTATGAGTCTCGAACTCGCTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGGATGTGTAGTCTGTTCTTT 921 106155044 106158550 - 0

CAGCAAACACAGCAACCCCAAACNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCTTGCTCAGCAAAGGTACTTG 922 106155044 106158550 + 0

GTGAAGAAGATCTTGCTTTGGGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNAGGCACAGGAAAAACATTTGCA 923 106157742 106157861 - 0

AATGTGCAGCAAAAGAGCATCATTGANNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNACTGAGTCTTGCCATAGT 924 106158077 106158150 + 0

GCAGCATGCTTTTGAGTGTCCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTGTTTTCTGGTGGTGCTGTGTGC 925 106155044 106158550 - 0

CTTCTTCAGAAAAGACACCAACCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGACCATAAGGCTCTTACTCTC 926 106158273 106158480 + 0

CACAGCTTGCAGGTGGATTCTCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGTCAAAACTGTGACTGGCCCTG 927 106155044 106158550 - 0

CTTCAGATATGGGATTTTCCTTCTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGAGTCACCTTCCAAATTACT 928 106158273 106158480 + 0

GCTGGGGTGTGGCTATCAAGTTCTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGAGTCTTGACAGGTGTATCC 929 106158273 106158480 - 0

GCAAAGGCACAGGGCAGATTAACGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTAGTATAATTGAGGTCTAAA 930 106162468 106162605 + 0

GCCTTTGGTCTTAAATCTTGGGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTTGTATGTGTGTGTGTTTCTGT 931 106163988 106164088 + 0

CCAATCGCCGGTGTGCCTTGAATNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTGTGTTTGGTGCGGGAGCGAG 932 106164823 106164875 + 0

CCCCCCACCCCAACCAAAACAAAANNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCGGGATTCCTTCCCACACCA 933 106164725 106164940 - 0

GCTCCGAGTAGAGTTTGTCAGCCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCACGCTGAACTCTCTTCCTTT 934 106164725 106164940 - 0

TTTGCCAGAAGCAAGATCCCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTGCACAGCCTATATAATGCTATCC 935 106180773 106180933 + 0

TTCTGGATCCAGCCCCTGACAGGCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNAGCGATTATACATCAGGAAG 936 106180773 106180933 - 0

SEQ feature_start feature_stop probe_ failure mip_sequence ID _position _position strand -flags GGCAGCAATTGTAACAACTTACTTGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNAGAATTATTCACTTTATAC 937 106182914 106183008 + 0 GAGGACAGCTTAGCAGCTGTTGAGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNAATATGAACACAGAGCACCA 938 106190761 106190911 + 0 GAAAACTCACTAGTATTTAGACCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNAGCACAGAAGTCCAAACATGC 939 106190761 106190911 - 0 GTCAAGACTTGCCGACAAAGGANNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGGATGAGCAGCTTCACGTTCTG 940 106193714 106194080 + 0 GTAAGACATTACAGCCTCAACTACNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTTTTTTCTCCTCCTGAGCTT 941 106193714 106194080 - 0 GCATTTGTAGATAAATGTGTTGTGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGAAGCCAAGAAAGCTGCAGC 942 106193714 106194080 + 0 GCCGAAAAGAACTCAGTACCTGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTGTTTTGTACGTGATGGGGCTG 943 106193918 106193967 - 0 CCCCAGCAGCAGCAGCCACANNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTTTCTGTTCTCTCTTACCCTGTCC 944 106196203 106196292 + 0 CCATGAACCCTTACCCTGGGCTTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCCACCAATCCATACATGAGAC 945 106196203 106197683 + 0 GCTGGGGCTGTGGTGGCTGCTTCTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGATATCTGAAGTGTGTGAAG 946 106196203 106197683 - 0 GCCAAGGTTTGGAAATAGCCAGAGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCAATGCAATGGAAACCTATC 947 106196203 106197683 + 0 CCTGCAGCTTGAGATGAGGTGGANNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGGCTGAGACTGGGGAGAATAG 948 106196203 106197683 - 0 GGTGAACATCATTCACCTTCTCACNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGTTTCAGCAGTTGTACCATT 949 106196203 106197683 + 0 GTGTATGGATGGGTGGTAGACTGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGAGTGGGATAAGGAGGCAATT 950 106196203 106197683 - 10 GCTTTCCCACACAGCTAATGGGTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNACCACCCAATCTGAGCAATCC 951 106196203 106197683 + 0 GTGATGCTAATGGTCAGGAAAAGCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCATGTTCAACAGCTCTCTTC 952 106196203 106197683 + 0 TCACCCCACCAGGATCTCCCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCAACGATGAGGTCTGGTCAGACAG 953 106196203 106197683 + 0 iCAGTTCTATCATGGTTAAGAGCTGGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTCAGGATCCAGAAAGCTC 954 106197125 106197218 - 0 CAGAGCCCACTTACCTGCGTTTCANNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNACATGGCTTGGCTCTTTGGG 955 106196203 106197683 + 0 GCAGCTCACGCTTTGCACACNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCTTCCTCTTTCTCACGGGCTTTTT 956 106196203 106197683 - 0 GAAGTTTCATGTGGCTCAGCAGGCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNACAAAAGGGGGTGATATCAT 957 106196203 106197683 - 0 CCACAACACTTCATAGACATCANNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGGACAGCCAGATATCAACTGTT 958 170837531 170837568 - 0 CAGTAGATCTCATTTTCCTATCAGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNACCATCCACAAAATGGATCC 959 140453092 140453191 + 0 CACAACAAAGCCTGCTGAAGATAGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNAGGGGGGAGGAGGTAGCAGA 960 148504736 148504801 + 10 GGGCTTTTTCTACTGGATTGTGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGCTCACTGACACCAGTGTGTCT 961 148506160 148506251 - 0 GTAAGCACAGCCCAGTGAATNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCCTACCTTTTGCATAGCAGTTTGG 962 148506400 148506485 + 0 GCTGGGAGGCAGTGAGTTCCTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGTCAGGCTTGATCACCTTTATCC 963 148507415 148507487 - 0 GGCACTGATAACCTGTATTCAGGTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTTTTCACCCTCCTTTTTTGA 964 148508716 148508816 - 0 GGAGGTTCTTCACTCATCACCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTTACTGTCCCAATGGTCAGCGGC 965 148511048 148511235 + 0 GTAGTTAGCTATTTAGTGATGCAANNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCTGGCTGTCCGAGAGTGTGA 966 148511048 148511235 - 0 GCATGAGAACTAAATAGGTCTTTGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCTCTAACCATGTTTACAACT 967 148511999 148512138 - 0 GCTTTGTTTTCATTTGTTTTAGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGCTCTCTGTTGGATTTGTAGCT 968 148512570 148512669 - 0 GCAGAGGGTACTTGAGAGGACTTTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTATTAGATTCTTTGTTTCAT 969 148516685 148516783 - 0 GTTTCTAAAAGGTTTCCATGTGTTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCAGATTTAGCATTTGGTCCA 970 148523544 148523730 + 0 CGTTTTCATTTTCTATCTTTGTTGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNACTTCCTCCTGAATGTACCC 971 148523544 148523730 - 0 GAGCCATATGCTTCTTCTCTTGGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTTTTTTTCTTTTAGGTGGAAG 972 148526828 148526931 - 0 TTGTTCTGTTGGAATAGTTCCTTGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTTACACCGCTTGTACCAGAA 973 117864785 117864951 - 0 GAGGACCAGCAACAGCAGCATNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGAAA I I I I I C I I I I I I I I I I I I I 974 117864785 117864951 - 0 GAATAATCACTAAGTTGGGCTCTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGAAGTAAAAATTCTGCAAACT 975 117866482 117866595 + 0 GGATCTGGCACCGCCCACCANNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCAGGAAAATGATCTTATTTTTTAT 976 117866604 117866713 - 0 CCTTTAGATTTATACAGCATNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNN I I I I I I I I I I I I I I I I I I ACAGTG 977 117868403 117868530 - 0

SEQ feature_start feature_stop probe_ failure mip_sequence ID _position _position strand -flags AGACTAGAAGGTTTGATTTATCTGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNAAGGACAAAAAAGACAGTAA 978 5069950 5070055 - 0 CAGGATCACAGCTAGGTGTCAGTGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNAGCAAGTATGATGAGCAAGC 979 5073739 5073781 + 0 CTTTCTACACATGCGTGGAAGTCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTTTTCATTTCTGACAACTTAC 980 112350168 112350333 + 0 GCTGGTTTATTCCTTTTCGACGGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTAAGCTATTCTTATTCCCTCT 981 112350168 112350333 - 0 GTTAGATGTCAGGGATACAGCCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCCTGAGTACCAATAAAGATTTG 982 112350747 112350893 + 0 AGTAACCTCTCCAGGAAGATTCATNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGTGTATAGTGCCTGGGCACT 983 112350747 112350893 - 0 CAGCTGGCCCGTGCTTTCACTANNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCTGTGTTGTGATCTCTCTGTTG 984 112352828 112352984 + 0 GAGTCTTTCCAAACACATGTTTGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCGCCCAGCCAGATTATATGTT 985 112352828 112352984 - 0 GCAAAGCTCAATGAAAACCTGCGCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNACAGACCTATTACATATGTT 986 112356153 112356245 + 0 GCCTCGGCCCTAACAATGTGGGCANNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGAAAAATAAATGTGAAGAAA 987 32413516 32413615 + 0 GCTGTGTTCCCTTGGGCTAGGGTTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTCAAATAGAATATGTGTCTT 988 32414197 32414308 - 0 GTCTTGAGGGAGAGTGAGCACTGGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGGTAAGCACACATGAAGGGG 989 32417797 32417956 + 0 GCAAACATGGTTCAAGAGCTCCTTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTCTTGTACGGTCGGCATCTG 990 32417797 32417956 - 0 AGGCTCAGTGTGGCTCACAGTCGCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTGGGGCCTGTCTGTGTGCTC 991 32421491 32421591 + 0 GAGCCCTGTGGACACCTCATGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCTGTTAACATTTATAATTGCAGT 992 119148874 119149011 + 0 GTTGGAATGTGGAGCCCATCTCACNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTACCGAATTTTCCAAGGTTA 993 119148874 119149011 - 0 GAGGCAAGGAGCAGAGGGAGCTCCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNAGTATTTTCAGATGCATCTG 994 119149218 119149335 + 0

ACAGATCTGTTTTCTGCAAAATCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGTACCTATGGTCCTAGTAGG 995 25378562 25378647 - 0 GACTGGGGAGGGCTTTCTTTGTGTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTGCACTGTAATAATCCAGAC 996 25380275 25380285 - 0 GCATATTACTGGTGCAGGACCATTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNATAAGGCCTGCTGAAAATGA 997 25398211 25398286 - 0 GTCCATTGGAAAGGGAGGCAANNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCCATTCTTCTCTTTTAATTGCCC 998 112888139 112888229 - 0 TCCGCTCAGTAATAGTCACTCTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCACGTAATAATATTGACTTTTC 999 112910747 112910847 + 0 GGTCACATAAGTCCTGGACTGCTTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGGCTAGAAATGTATGGTCAG 1000 112915440 112915540 - 10 GGACAACAGAATCATTCATGGGGGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCATAAACTAAAAACAGAAAC 1001 112926228 112926328 - 0 GCGCAGGATTGAAGAAGAGCAGGTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGATGTTTCCTTCGTAGGTGT 1002 112926848 112926919 + 0 GGCCAGGTCTCTGTGAACACACTGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCACAAAATAGCCGTATAAAA 1003 28592612 28592705 + 0 AAGGAGCATTAAAAATGTAAAACTCAAGTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTTTTCGTGGAAGTGGG 1004 28602314 28602426 + 0 GTGGAAGGACAGCAACAAAGATGCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGCACGTACTCACCATTTGTC 1005 28608022 28608130 - 0 GCTTCAGAGATGAAATGATGAGTCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCATTCCATTCTTACCAAACT 1006 28608200 28608360 + 0 TCTGCAGCATTTCTTTTCCATTGGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGAAAGCCAGCTACAGATGGT 1007 28608200 28608360 - 0 GCAACAAAAGAGTGTCACTCAGCGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNAGAGGAAAGAATAATGAATT 1008 28608437 28608546 + 0 CTGCTCGACACCCACTGTCCAAANNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGTGGGGAATTCCTGATGGTGG 1009 28609629 28609815 + 0 GCTGTCATCAGATTGGAAGTTAGGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNACCCTTTTATGGCTTCACTC 1010 28609629 28609815 + 0 CGTGTGAAATAAGCTCACTGGCTGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNAAGAGGCATCAATGTCCTTA 1011 28610070 28610185 + 0 GCAGATGATGGGCTCCCGGAAGACNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNAAGAGGATGGCTAGGCGAGG 1012 90631835 90631946 + 0 GAGATAATAGTGGTCCCACTGCAGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTGGTGATGGGCTTGGTCCAG 1013 90631835 90631946 + 0 GACAGAAGCAGGGAGGAGAGATGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNAGGGGAGGGAGAGATGGGGGT 1014 7572925 7573012 + 0 GCTGGGAAGGAGCCAGGGGGGANNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCAAACAATTGTAACTTGAACCA 1015 7573973 7574036 - 0 GTCTAACACTCAAAATGCCGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTTCACTTTTATCACCTTTCCTTGC 1016 7576850 7576934 - 0 ACCAGGCTCCATCTACTCCCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTTCTCTTCCTCTGTGCGCCGGTCT 1017 7577014 7577158 + 0 CCAAGGGTGCAGTTATGCCTCAGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGCTTTGAGGTGCGTGTTTGTG 1018 7577014 7577158 - 0

GTAGTGGATGGTGGTACAGTCAGANNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNAGAGGCAAGCAGAGGCTGGG 1019 7577495 7577613 + 0 GCGGCATGAACCGGAGGCCCATNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNAAAAAAAAAAAAAAAGGCCTCC 1020 7577495 7577613 - 0 CCTGGGGACCCTGGGCAACCANNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNAACCAGACCTCAGGCGGCTCATA 1021 7578168 7578295 + 0 GTGAGCAGTAGGGGGGCTTTCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGAGTGGAAGGAAATTTGCGTGTG 1022 7578115 7578211 - 0 GTTGAGGGCAGGGGAGTACTGTAGGANNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNATGGTGGGGGCAGCGCCT 1023 7578364 7578560 + 0 GGGCTGGAGAGACGACAGGGCTGGTTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCATGGCCATCTACAAGCA 1024 7578364 7578560 - 0 TTCCACACCCCCGCCCGGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCTGCCGTCTTCCAGTTGCTTTATCTG 1025 7578364 7578560 - 0 TTTCTGGGAAGGGACAGAAGATGANNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCAAACAAAAGAAATGCAGGG 1026 7579308 7579600 + 0

GTAGGAGCTGCTGGTGCAGGGGCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTCAGGGCAACTGACCGTGCAA 1027 7579308 7579600 + 0 GCATCAAATCATCCATTGCTTGGGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNAGGAGGGGGCTGGTGCAGGG 1028 7579443 7579523 + 0 ACCCAGGTCCAGATGAAGCTCCCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTGGGGACCTGGAGGGCTGGGG 1029 7579308 7579600 - 0 AAGGGCAGGCCCACCACCCCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTCATGCTGGATCCCCACTTTTCCT 1030 7579812 7579915 - 0 GCCTTCCAATTGGCCTTGTGCCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGCCTTCTCAGAGAATTTTTTAG 1031 58740352 58740920 + 0 AAAAAATTTATCCCAGAACTCAACNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCTCTCGAGCTATCTCAGCTG 1032 58740352 58740920 - 0 AGCCTGCAAGTCTCCCCACAACCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTGAAGATGTCAACTCCTGGCC 1033 58740352 58740920 + 0 CAATTTTCTTCAAGTGGTTCTGGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTCAATTTCTTGGGCTTTCATT 1034 58740352 58740920 - 0 GATGTTGAACTTTTTTTAAGGGGANNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNATGCGACGCAGACTTAGGGG 1035 58740352 58740920 + 0 :GTCTATGCTTCTTCATCAGGGGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGTTTTCCTGTGTTGATGAAGT 1036 58740352 58740920 - 0

AGCTCGCGGCCGTCCAGCACNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGGTCCCCGGCGGCTGTGGTGTGAG 1037 74732956 74732961 + 0 TTTCTGCTCCCTGGACAACCCGGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCTCCCTAAAGGAAATCACGCT 1038 42531868 42531969 + 0 GGCCTGCCTCCAGGGCTGGACTGANNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNAAGAAGACAAGAAACGCAAA 1039 13054525 13054730 + 0 CTTGCCCCCTGCCAGCCCTGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNATCTTTGTCCTCATCATCCTCCTT 1040 13054525 13054730 - 0 GCAACTGCGCGTGAGGCGCGCGGCTGTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGAAGGTGCTGGAGCTG 1041 33792300 33792469 - 0 TGACCGCCTGCGCAAGCGGGTGGANNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNAAGGCCAAGAAGTCGGTGGA 1042 33792244 33793326 - 0 GCGGGGCTCCTGCTTGATCACCAGCGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGCGGGTGCGGGTGCGG 1043 33792674 33792865 + 0 TCATGCCCGGGGGAGCGCACGGGCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGGCCAAGGCGGCCGTG 1044 33792970 33793010 - 0

GCTGATGTCGATGGACGTCTCGTGCTCGCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCTTGGCCTTCTCCTGC 1045 33793025 33793090 + 0 GCAGGTGGCTGCTCATCGGGGGCCGCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGGTGGGGCGGGAGGCT 1046 33793243 33793300 + 0 GCCACCCGACAGCGAGATGGGCANNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGGCCTGAAACTGATGGCTGTG 1047 31021087 31021727 + 0 TCCCCATCTGCCAGGCACATCCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCAGATCTCCGAACCAGAGCCAG 1048 31021087 31021727 + 0 CCTGGGACACACAAGCCACTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTTTGCATCCTTAGCAACCCCTGCT 1049 31021087 31021727 - 0 GAGCAGGCGGCCTCTGCATCCTTTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCCGAATTCCCAGTTGAGTCT 1050 31021087 31021727 + 0 GCCCTGCTGGGTCAGTCTTAGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCAGGCTAGGAATTCTGTCTGGAG 1051 31021087 31021727 - 0 CACAGCCCACTAAAGAGGAGCCCANNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTCAGGAAACTGTGGATCAGG 1052 31021087 31021727 + 0

CGGGGTTGGACTGGCGCCAGGANNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTAGGTCAGATCACCCAGTCAGT 1053 31022233 31025152 + 0 GTGGTGATGGTGGTGAGGCCTGTGGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGAGGGGCGAGAGGTCA 1054 31022435 31022452 + 0 GGTGGGGATGATCCGGGGGCATATNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTCCGATGGCAGTGGTGGCCG 1055 31022322 31022412 - 0 TGCCAGGCCTTGCCCCTACTGTCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGGAACTGCCATGTCCAGAGCT 1056 31022233 31025152 + 0 GTACACTTTCCAGGGGTGCTCGGGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCTGTAGCCCTCTGTAGTAGG 1057 31022233 31025152 - 0 GGATCCTGTAAATGTGACCCCCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGTGAGTCTGGCACCACTTCCTG 1058 31022233 31025152 + 0 GCAAGGCCTGGCATGGCTGGTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNACCATTGTCTGCAGGAACGGTGG 1059 31022233 31025152 - 0

GGTAGTGAAACAGCCCAAACCAGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGCAGAACAGAGCATTTGATGA 1060 31022233 31025152 + 0

GCTTGGCCAGTTCCTTTCTCTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTATCACTTTCCCTCATAGGAGGG 1061 31022233 31025152 - 0

GGAGACTCTGAAGCACTGAGTCCTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCTGCATTGCCTGGGGATTTG 1062 31022233 31025152 + 0

CGATGGGATGGGTATCCAATGCANNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNAGGATCTAGACCCTCCTCAGC 1063 31022233 31025152 - 0

GTTGACAGTAACTGCCATTGCTGTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCTTTGTCACTGCAGCTTCTC 1064 31022233 31025152 - 0

GGTGACCTTCAAAGTCAGAGGCTGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNATCTGTCCTTGTAACCAGAC 1065 31022233 31025152 - 0

GTAGCTTGCCCCTAGAGAAGGTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTGGGTGTCTCGAGTATGTGCGG 1066 31022233 31025152 + 0

GTGGGGCAGATTGGTTCCAATTGGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGGCTCTTGGCTGGTACTCAG 1067 31022233 31025152 - 0

GCAACTGCATCACAAGTGGGTTAGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGCCACTGTTTTTTCCAAGAC 1068 31022233 31025152 - 0

CCCTCCATCCAGTGACAAATCCCANNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTGGAAGCAGCCCCAGTTCTT 1069 31022233 31025152 + 10

GCAGTTCTCTTCCTTTAGTTGTGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNAGGCACTGGTCTTGCCAGGAT 1070 31022233 31025152 + 0

GCGAGCCATGGCTCTGGTCTTTTGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCTGGGTGGCCTCAATCCTGG 1071 31022233 31025152 - 0

CCTCGTTTCTCATCTCCAAATGTGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCTAGGAAACTGGAAGAAATG 1072 31022233 31025152 + 0

AACCCTTCAGCGCCCCAGGCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCCCAGGAGATCTTACTACCTCGAG 1073 31022233 31025152 + 0

GTGGGGTACAGACTCCAAGGGAAGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNAGGCCAAGGGAAGAAGCTTT 1074 31022233 31025152 + 0

GCCGAGAACAGGAAAGCTACTGGGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTTCCCAGTGGGAAGTTGGGA 1075 31022233 31025152 + 0

GAAGGGGCTCAGTGAGCCTCTGGANNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGAGAAGACTTTTGTGGGGGG 1076 31022233 31025152 + 0

CTCTAGCTCTCCCACCTTTCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCTTGCCCTTCTGGAAATTACCCC 1077 31022233 31025152 + 0

GCAGCACGGTGGAAAGCATCTCGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTCCAACTGAGTTCCACCAGCT 1078 31022233 31025152 + 0

GCTCTGTGTATTGTGCCTTGTGGTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCACAGTGCATCACTTTCCTT 1079 31022233 31025152 + 0

GAGGTCAATGGATCTCACCAAAGCCANNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCAAGAAACCATGATCTCT 1080 57484402 57484481 - 0

GGTGGTAGGAGGGCGAGCTGGCTTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGGTTCGGGAGGCTGGGGTTG 1081 36164474 36164925 + 0

GCGGCGGCAGGTAGGTGTGGTAGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNACCATGGAGAACTGGTAGGAG 1082 36164474 36164925 + 0

GGTGACCGGCGTCGGGGAGTAGGTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTTGCGACGAGCCGGGGTAGG 1083 36164474 36164925 + 0

GCGGGGGTCGGAGATGGAGGGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGGGGTAGGGCGGCGGCAGGTAGG 1084 36164474 36164925 + 0

GCGGAAGTGAGTAGGAGGTTGCGGANNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGTCGGGGAGTAGGTGAAGG 1085 36164474 36164925 + 0

GTCCAGGAGACTAGAGGTGCATGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTCCATTGCCTCTCCTTCTGTG 1086 36171591 36171765 - 0

ACGCCCATTTCACCTGGACGTGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCATTTTTTAAATCCCACCCCAC 1087 36171591 36171765 - 0

GAGGCACGAGGGTTGGGCGTGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGGGAAGGTGTGTGCACATGGGGG 1088 36206704 36206900 + 0

CGGGCTTGGTCTGATCATCTAGTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGGGTTAAAGGCAGTGGAGTGG 1089 36206704 36206900 + 0

GCGGCGCACAGCCATGAGGGTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTCTTCCCTCCCTCCTTCCCTCCC 1090 36206704 36206900 - 0

GGGCTGGTACACCCTCCAGGCTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTTTTGTTCTCTATCGTGTCCCC 1091 36231767 36231880 - 0

CATCATTGCCAGCCATCACAGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTGGGTTTGTTGCCATGAAACGTG 1092 36252844 36253026 + 0

GCTGAGCTGAGAAATGCTACCGCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNATCACTACACAAATGCCCTAA 1093 36252844 36253026 - 0

GCAGAGGAAGTTGGGGCTGTCGGTGCGCANNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCTGTCCTCCCACCACC 1094 36259157 36259187 + 0

GGCCAGCACCTCCACCATGCTGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGTCTTGTTGCAGCGCCAGTGCG 1095 36259192 36259400 + 0

GCCAGTGACGTGACTGAGCACANNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTTTCGCCGTGAGGAAGATGCGG 1096 44514777 44514876 - 0

CATGGAATATGTCAGCAGCATGACNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCAAACAAACCTGGCTAAACG 1097 44524444 44524480 + 0

GCATGCGTGTGGAGGAGGGGACTGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNAATGGAGCAGTGCAGGAGGG 1098 15833798 15834016 + 0

GGCCAATAGTTGAAAATTACTCACNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGCTTGCGTCAGGGTCATAGT 1099 15833798 15834016 - 0

AAATTCAGGAAAAGAAACCAGCCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNAACAGAAACAGAACAACAAAC 1100 15836703 15836772 - 0

TTTCCTCAATTGTTCCACTGCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGCATATCATTTGATTTTTGGTTT 1101 15838328 15838442 + 0

GCTTCCAGGTCTTTGGAGCAAGAGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGTACATGGTGGGTCCAGCTT 1102 39911360 39911656 + 0

GTAAAATGAAAAGTGCGCCCAACNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTTCTGCCTCTGCAATGGTGAC 1103 39911360 39911656 + 0

GTAAGGAGCTGTTAGATCTGGTGGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGAAATTGAAAATGTCCTCCC 1104 39911360 39911656 - 0

CGTTCTCAACAGCATCGTGCAGAGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNAGACCATTTCTTGAACTTTG 1105 39914617 39914770 + 0

CTTATGGTGCTGACCCCACCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTGCCCAGCTTTGCCTGTTGCTTTT 1106 39914617 39914770 - 0

TCGCCCAGTCCAATGCCTTGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTCCTGCTGGTTTTGGTGCCATCTG 1107 39931589 39934460 + 0

CATGTGGTCAGCTTTGGAAGCATCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGAGGGAGCAGTGCTGATGAT 1108 39931589 39934460 + 0

CAGCAGCGGAGTTCATCATGCCCGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCTCCAGGAAATGGTTGTGCT 1109 39931589 39934460 - 0

CAGGGGTTTTCTTCCCCTCTGGGCCTGAGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTTTCTGTGTCTGAGGA 1110 48649515 48649604 + 0

GCTGGAAGCTTCTCAAATGGATGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTGGCCTACTACAGGGACGCTG 1111 48649516 48649738 + 0

GGTGTGGAGGACACCAGAGCAGGANNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTGGAGTTACCTGGGGAGTGT 1112 48649516 48649738 - 0

GCAGCTCTGCCTCTTTCCGTTTTGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTGTGTGGATGGCCTTTGGAG 1113 53431940 53432902 + 0

GCACTGCCTGTGGCTTACTTTCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNATCTGCAGTCCATGGGCCTGAG 1114 53431940 53432902 + 0

GCCTTCAGGTCACTGGCCCCANNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGCTAGGTGGTAAGGTGGTGGCTG 1115 53431940 53432902 + 0

CCAGTACTGAGCCTGTCCAGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTTTCTCATCCCAGCGCCGTGCCTT 1116 53431940 53432902 + 0

GACAAGGGCATTGCCACAAGCATANNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGGGGGAAGAGAGAAGAGGGG 1117 53431940 53432902 + 0

CTCACCTCCAGGTAGTCAAGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNATCAATCACTAGCTTGGCCCCCT 1118 53431940 53432902 + 0

GCCGCATTGCCTTTGGAGGCCANNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCAGGTGAAGCCTACAGATGAGA 1119 53431940 53432902 - 0

GCTTTTGGAAGCTGGCTCAGGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGCCTGTCTTCTCCGAGTCCACAA 1120 53431940 53432902 + 0

GGGTCAGGCCAGTGTTCAAGGGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNACCAAGGTTTTGGGCAAGAACA 1121 53431940 53432902 - 0

GGCTATTGTGTGACCAACTTGGTCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTGGCACTAAATCTTAGCATT 1122 123181202 123181359 + 0

GGTGAAACTAATCTAACAGACACANNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGCCTCTCATTGGCTCGTTTT 1123 123181202 123181359 - 0

GCAAGTTTGCATATTTCGTGGTGTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGAAATGATGTGTTTTTTTAC 1124 123182853 123182930 + 0

AAGATGTGCCCTTCAGACTGCTTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTTATGCATCGTTTTTCCTTCC 1125 123184036 123184161 + 0

CCAGTCGGTTCAAGGTTAGTATTANNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGAAGTTGAAAATACATAGAG 1126 123184969 123185250 + 0

GTGTCTATGACCCTTGACAAAGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNAAGAGCTTAATTCCAAACTGGA 1127 123184969 123185250 + 0

GCATATTTGCACTAATGTTCAGATNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCTTTTCTCTTGCTTTCCTTT 1128 123184969 123185250 + 0

GAAATAAGCAGTAACAGGTGCTTNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGCCTTAGAAAATGAGTAACAG 1129 123189975 123190088 - 0

ACCATGTCAGTCATTAGTGGAATCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGTATCAAAGCTAACAGTTTC 1130 123220395 123220624 + 0

CCACCAGCTAGCAAAGAATTTCGGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNAAAGAGAATAAATTATATCC 1131 123220395 123220624 - 0

CCGGCAGCAACAGAGACCTTGAAANNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTGTCAAGCTCAGTTGAACAG 1132 133511647 133511790 + 0

GCCACTTTAAGTCTCAAGAAATGCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCGCTGCCACCTTCTGGTTTT 1133 133511647 133511790 - 0

GCATTTCATCATCATCATAAAGGGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNCTACCACTGTGCATTGCATG 1134 133527529 133527670 + 0

GTATGTGACTTTCTAAGGCTGTATNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGGTTTCTCTCGTATTTGAGC 1135 133527529 133527670 - 0

CCACGTTTCAGCCACTTTTCAGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTTAGTTTGCTTACTAATTTTTG 1136 133527932 133527989 + 0

GGGGAGGAAGAAAATGAAGCACGANNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGAAATGTTAAGTAAGCTTGA 1137 133547847 133548010 + 0

GCCTGGTGTCACTAGGGCTGCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNAAACAAACAACAAAAAAACAAAA 1138 133547847 133548010 - 0

ATGCAGGAAAATTAACATTCAGAATCCNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNTGTTGCATAACAAATATAAAAACTACA 1139 133549044 133549153 - 0

GACTGCAAAGTGTACATTTCTGNNNNCTTCAGCTTCCCGATATCCGACGGTAGTGTNNNNGTTTAGGGAAATAGACAACTGT 1140 133551219 133551319 - 0

Reference List

1. Diepen S Van, Katz JN, Albert NM, Henry TD, Jacobs AK, Kapur NK, Kilic A, Menon V, Ohman EM, Sweitzer NK, Thiele H, Washam JB, Cohen MG. Contemporary Management of Cardiogenic Shock: A Scientific Statement from the American Heart Association. Circulation.

2. Helgestad OKL, Josiassen J, Hassager C, Jensen LO, Holmvang L, S0rensen A, Frydland M, Lassen AT, Udesen NLJ, Schmidt H, Ravn HB, M0ller JE. Temporal trends in incidence and patient characteristics in cardiogenic shock following acute myocardial infarction from 2010 to 2017: a Danish cohort study. Eur J Heart Fail 2019;21 ;(11): 1370-1378.

3. Jentzer JC, Lawler PR, Diepen S Van, Henry TD, Menon V, Baran DA, Dzavik V, Barsness GW, Holmes DR, Kashani KB. Systemic Inflammatory Response Syndrome Is Associated With Increased Mortality Across the Spectrum of Shock Severity in Cardiac Intensive Care Patients. Circ Cardiovasc Qual Outcomes 2020;13;(12):1033-1045.

4. Andrie RP, Becher UM, Frommold R, Tiyerili V, Schrickel JW, Nickenig G, Schwab JO. Interleukin-6 is the strongest predictor of 30-day mortality in patients with cardiogenic shock due to myocardial infarction. Crit Care 2012;16;(4).

5. Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman P V., Mar BG, Lindsley RC, Mermel CH, Burtt N, Chavez A, Higgins JM, Moltchanov V, Kuo FC, Kluk MJ, Henderson B, Kinnunen L, Koistinen HA, Ladenvall C, Getz G, Correa A, Banahan BF, Gabriel S, Kathiresan S, Stringham HM, McCarthy Ml, Boehnke M, Tuomilehto J, Haiman C, Groop L, Atzmon G, Wilson JG, Neuberg D, Altshuler D, Ebert BL. Age- related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 2014;371 ;(26):2488-2498.

6. Acuna-Hidalgo R, Sengul H, Steehouwer M, Vorst M van de, Vermeulen SH, Kiemeney LALM, Veltman JA, Gilissen C, Hoischen A. Ultra-sensitive sequencing identifies high prevalence of clonal hematopoiesis-associated mutations throughout adult life. Am J Hum Genet 2017;101;(1):50-64. 7. Young AL, Challen GA, Birmann BM, Druley TE. Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults. Nat Commun 2016;7:12484.

8. Genovese G, Kahler AK, Handsaker RE, Lindberg J, Rose SA, Bakhoum SF, Chambert K, Mick E, Neale BM, Fromer M, Purcell SM, Svantesson O, Landen M, Hbglund M, Lehmann S, Gabriel SB, Moran JL, Lander ES, Sullivan PF, Sklar P, Grbnberg H, Hultman CM, McCarroll SA. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med 2014;371 ;(26):2477-2487.

9. Dorsheimer L, Assmus B, Rasper T, Ortmann CA, Ecke A, Abou-EI-Ardat K, Schmid T, Brune B, Wagner S, Serve H, Hoffmann J, Seeger F, Dimmeler S, Zeiher AM, Rieger MA. Association of mutations contributing to clonal hematopoiesis with prognosis in chronic ischemic heart failure. JAMA Cardiol 2019;4;(1):25-33.

10. Jaiswal S, Natarajan P, Silver AJ, Gibson CJ, Bick AG, Shvartz E, McConkey M, Gupta N, Gabriel S, Ardissino D, Baber U, Mehran R, Fuster , Danesh J, Frossard

P, Saleheen D, Melander O, Sukhova GK, Neuberg D, Libby P, Kathiresan S, Ebert BL. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N Engl J Med 2017;377;(2):111-121.

11. Jaiswal S, Libby P. Clonal haematopoiesis: connecting ageing and inflammation in cardiovascular disease. Nature Reviews Cardiology.

12. Yu B, Roberts MB, Raffield LM, Zekavat SM, Nguyen NQH, Biggs ML, Brown MR, Griffin G, Desai P, Correa A, Morrison AC, Shah AM, Niroula A, Uddin MM, Honigberg MC, Ebert BL, Psaty BM, Whitsei EA, Manson JAE, Kooperberg C, Bick

AG, Ballantyne CM, Reiner AP, Natarajan P, Eaton CB. Supplemental association of clonal hematopoiesis with incident heart failure. J Am Coll Cardiol 2021 ;78;(1):42-52.

13. Sano S, Oshima K, Wang Y, Katanasaka Y, Sano M, Walsh K. CRISPR- mediated gene editing to assess the roles of TET2 and DNMT3A in clonal hematopoiesis and cardiovascular disease. Circ Res 2018;123;(3):335-341.

14. Baran DA, Grines CL, Bailey S, Burkhoff D, Hall SA, Henry TD, Hollenberg SM, Kapur NK, O’Neill W, Ornato JP, Stelling K, Thiele H, Diepen S, Naidu SS. SCAI clinical expert consensus statement on the classification of cardiogenic shock. Catheter Cardiovasc Interv 2019;94;(1):29-37. 15. Medeiros JJF, Capo-Chichi J-M, Shlush LI, Dick JE, Arruda A, Minden MD, Abelson S. SmMIP-tools: a computational toolset for processing and analysis of singlemolecule molecular inversion probes derived data 2. bioRxiv 2021 :2021.06.03.446993.

16. Pascual-Figal DA, Bayes-Genis A, Diez-Diez M, Hernandez-Vicente A, Vazquez-Andres D, la Barrera J de, Vazquez E, Quintas A, Zuriaga MA, Asensio- Lopez MC, Dopazo A, Sanchez-Cabo F, Fuster JJ. Clonal hematopoiesis and risk of progression of heart failure with reduced left ventricular ejection fraction. J Am Coll Cardiol 2021 ;77;(14):1747-1759.

17. Watson CJ, Papula AL, Poon GYP, Wong WH, Young AL, Druley TE, Fisher DS, Blundell JR. The evolutionary dynamics and fitness landscape of clonal hematopoiesis. Science (80- ) 2020;367;(6485): 1449-1454.

18. Abdel-Wahab O, Adli M, LaFave LM, Gao J, Hricik T, Shih AH, Pandey S, Patel JP, Chung YR, Koche R, Perna F, Zhao X, Taylor JE, Park CY, Carroll M, Melnick A, Nimer SD, Jaffe JD, Aifantis I, Bernstein BE, Levine RL. ASXL1 mutations promote myeloid transformation through loss of PRC2-mediated gene repression. Cancer Cell 2012;22;(2):180-193.

19. Assmus B, Cremer S, Kirschbaum K, Culmann D, Kiefer K, Dorsheimer L, Rasper T, Abou-EI-Ardat K, Herrmann E, Berkowitsch A, Hoffmann J, Seeger F, Mas- Peiro S, Rieger MA, Dimmeler S, Zeiher AM. Clonal haematopoiesis in chronic ischaemic heart failure: prognostic role of clone size for DNMT3A- and TET2-driver gene mutations. Eur Heart J 2021 ;42;(3):257-265.

20. Geppert A, Dorninger A, Delle-Karth G, Zorn G, Heinz G, Huber K. Plasma concentrations of interleukin-6, organ failure, vasopressor support, and successful coronary revascularization in predicting 30-day mortality of patients with cardiogenic shock complicating acute myocardial infarction. Crit Care Mec/ 2006;34;(8):2035-2042.

21. Heeschen C, Dimmeler S, Hamm CW, Brand MJ van den, Boersma E, Zeiher AM, Simoons ML. Soluble CD40 ligand in acute coronary syndromes. N Engl J Med 2003;348;(12):1104-1111.

22. Shami A, Edsfeldt A, Bengtsson E, Nilsson J, Shore AC, Natali A, Khan F, Lutgens E, Gongalves I. Soluble CD40 levels in plasma are associated with cardiovascular disease and in carotid plaques with a vulnerable phenotype. J Stroke 2021 ; 23; (3): 367-376.

23. Milner JD, Orekov T, Ward JM, Cheng L, Torres-Velez F, Junttila I, Sun G, Buller M, Morris SC, Finkelman FD, Paul WE. Sustained IL-4 exposure leads to a novel pathway for hemophagocytosis, inflammation, and tissue macrophage accumulation. Blood 2010;116;(14):2476-2483.

24. Qin Y, Zhang C. The regulatory role of IFN-y on the proliferation and differentiation of hematopoietic stem and progenitor cells. Stem cell Rev reports 2017;13;(6):705-712.

25. Baldridge MT, King KY, Boles NC, Weksberg DC, Goodell MA. Quiescent haematopoietic stem cells are activated by IFN-gamma in response to chronic infection. Nature 2010;465;(7299):793-797.

26. Agarwal P, Li H, Choi K, Hueneman K, He J, Weiner RS, Starczynowski DT, Bhatia R. TNF-a-induced alterations in stromal progenitors enhance leukemic stem cell growth via CXCR2 signaling. Cell Rep 2021 ; 36; (2): 109386.

27. Abegunde SO, Buckstein R, Wells RA, Rauh MJ. An inflammatory environment containing TNFa favors Tet2-mutant clonal hematopoiesis. Exp Hematol 2018;59:60- 65.

28. Broek I Vande, Asosingh K, Vanderkerken K, Straetmans N, Camp B Van, Riet I Van. Chemokine receptor CCR2 is expressed by human multiple myeloma cells and mediates migration to bone marrow stromal cell-produced monocyte chemotactic proteins MCP-1 , -2 and -3. BrJ Cancer 2003; 88; (6): 855-862.

29. Bick AG, Pirruccello JP, Griffin GK, Gupta N, Gabriel S, Saleheen D, Libby P, Kathiresan S, Natarajan P. Genetic interleukin 6 signaling deficiency attenuates cardiovascular risk in clonal hematopoiesis. Circulation 2020;141 ;(2):124-131. s1. Mehra MR, Canter CE, Hannan MM, et al. The 2016 International Society for Heart Lung Transplantation listing criteria for heart transplantation : A 10-year update. J Heart Lung Transplant. 2016;35(1):1-23. doi:10.1016/j.healun.2015.10.023 s2. Organ Transplant | US Organ Donation System | UNOS. Accessed January 27,

2022. https://unos.org/transplant/ s3. Khush KK, Cherikh WS, Chambers DC, et al. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Thirty-sixth adult heart transplantation report — 2019; focus theme: Donor and recipient size match. J Heart Lung Transplant. 2019;38(10):1056-1066. doi:10.1016/J.HEALUN.2019.08.004 s4. Costanzo MR, Force T, Rosa M, et al. The International Society of Heart and Lung Transplantation Guidelines for the care of heart transplant recipients. J Heart Lung Transplant. 2010;29(8):914-956. doi:10.1016/j.healun.2010.05.034 s5. Kittleson MM, Kobashigawa JA. Long-term care of the heart transplant recipient. Curr Opin Organ Transplant. 2014;19(5):515-524. doi: 10.1097/MOT.0000000000000117 s6. Giarraputo A, Barison I, Fedrigo M, et al. A changing paradigm in heart transplantation: An integrative approach for invasive and non-invasive allograft rejection monitoring. Biomolecules. 2021 ;11 (2):1-17. doi:10.3390/biom11020201 s7. Jaiswal S, Fontanillas P, Flannick J, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371 (26):2488-2498. doi: 10.1056/NEJMoa1408617 s8. Jaiswal S, Natarajan P, Silver AJ, et al. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N Engl J Med. 2017;377(2):111-121. doi: 10.1056/NEJMoa1701719 s9. Bhattacharya R, Zekavat SM, Haessler J, et al. Clonal hematopoiesis is associated with higher risk of stroke. Stroke. 2020;53(3):788-797. doi:10.1161/strokeaha.121.037388 s10. Dorsheimer L, Assmus B, Rasper T, et al. Association of mutations contributing to clonal hematopoiesis with prognosis in chronic ischemic heart failure. JAMA Cardiol. 2019;4(1):25-33. doi:10.1001/jamacardio.2018.3965 s11 . Bolton KL, Koh Y, Foote MB, et al. Clonal hematopoiesis is associated with risk of severe Covid-19. Nat Common. 2021 ;12(1):5975. doi:10.1038/s41467-021 -26138-6 s12. Genovese G, Kahler AK, Handsaker RE, et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med. 2014;371 (26):2477-2487. doi:10.1056/NEJMoa1409405 s13. Dawoud AAZ, Gilbert RD, Tapper WJ, Cross NCP. Clonal myelopoiesis promotes adverse outcomes in chronic kidney disease. Leukemia. 2022;36(2):507- 515. doi: 10.1038/S41375-021 -01382-3 s14. Pascual-Figal DA, Bayes-Genis A, Diez-Diez M, et al. Clonal hematopoiesis and risk of progression of heart failure with reduced left ventricular ejection fraction. J Am Coll Cardiol. 2021 ;77(14):1747-1759. doi: 10.1016/j.jacc.2O21 .02.028 s15. Sano S, Oshima K, Wang Y, Katanasaka Y, Sano M, Walsh K. CRISPR- mediated gene editing to assess the roles of TET2 and DNMT3A in clonal hematopoiesis and cardiovascular disease. Circ Res. 2018;123(3):335-341. doi: 10.1161 /CIRCRESAHA.118.313225 s16. Medeiros JJF, Capo-Chichi J-M, Shlush LI, et al. SmMIP-tools: a computational toolset for processing and analysis of single-molecule molecular inversion probes- derived data. Bioinformatics. 2022;38(8):2088-2095. doi: 10.1093/bioinformatics/btac081 s17. Jaiswal S, Libby P. Clonal haematopoiesis: connecting ageing and inflammation in cardiovascular disease. Nat Rev Cardiol. 2020;17(3):137-144. doi: 10.1038/S41569-019-0247-5 s18. Sano S, Oshima K, Wang Y, et al. TET2-mediated clonal hematopoiesis accelerates heart failure through a mechanism involving the IL-i p/NLRP3 inflammasome. J Am Coll Cardiol. 2018;71 (8):875-886. doi:10.1016/j.jacc.2017.12.037 s19. Sano S, Wang Y, Yura Y, et al. JAK2-V617F-Mediated clonal hematopoiesis accelerates pathological remodeling in murine heart failure. JACC Basic Transl Sci. 2019;4(6):684-697. doi:10.1016/j.jacbts.2019.05.013 s20. Sano S, Wang Y, Ogawa H, et al. TP53-mediated therapy-related clonal hematopoiesis contributes to doxorubicin-induced cardiomyopathy by augmenting a neutrophil-mediated cytotoxic response. JCI Insight. 2021 ;6(13):e146076. doi: 10.1172/jci. insight.146076 s21. Yura Y, Miura-Yura E, Katanasaka Y, et al. The Cancer Therapy-Related Clonal Hematopoiesis Driver Gene Ppmld Promotes Inflammation and Non-lschemic Heart Failure in Mice. Circ Res. 2021 ;129(6):684-698. doi:10.1161/CIRCRESAHA.121.319314 s22. Fuster JJ, MacLauchlan S, Zuriaga MA, et al. Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science. 2017;355(6327):842-847. doi:10.1126/science.aag1381 s23. Nikolova AP, Kobashigawa JA. Cardiac Allograft Vasculopathy: The enduring enemy of cardiac transplantation. Transplantation. 2019;103(7):1338-1348. doi: 10.1097/TP.0000000000002704 s24. Chih S, Chong AY, Mielniczuk LM, Bhatt DL, Beanlands RSB. Allograft vasculopathy: the achilles’ heel of heart transplantation. J Am Coll Cardiol. 2016;68(1):80-91. doi:10.1016/J.JACC.2016.04.033 s25. Lee F, Nair V, Chih S. Cardiac allograft vasculopathy: Insights on pathogenesis and therapy. Clin Transplant. 2020;34(3):e13794. doi:10.1111/CTR.13794 s26. Fahmy NM, Yamani MH, Starling RC, et al. Chemokine and chemokine receptor gene expression indicates acute rejection of human cardiac transplants. Transplantation. 2003;75(1):72-78. doi: 10.1097/00007890-200301150-00013 s27. Tarazon E, Corbacho-Alonso N, G. Barderas M, et al. Plasma CD5L and non- invasive diagnosis of acute heart rejection. J Heart Lung Transplant. 2020;39(3):257- 266. doi:10.1016/J.HEALUN.2019.11.004 s28. Jones IKA, Orloff S, Burg JM, et al. Blocking the IL-1 receptor reduces cardiac transplant ischemia and reperfusion injury and mitigates CMV-accelerated chronic rejection. Am J Transplant. 2021 ;21 (1):44-59. doi:10.1111/ajt.16149 s29. Alyaydin E, Welp H, Reinecke H, Tuleta I. Predisposing factors for late mortality in heart transplant patients. Cardiol J. 2021 ;28(5):746-757. doi:10.5603/CJ.A2020.0011 s30. Newell LF, Dunlap J, Gatter K, et al. Graft-versus-host disease after liver transplantation is associated with bone marrow failure, hemophagocytosis, and

DNMT3A mutations. Am J Transplant. 2021 ;21 (12):3894-3906.

Claims

CLAIMS:

1. A method of predicting the risk of a disease condition of a solid organ in a patient, the method comprising: a) receiving a sample from the patient containing hematopoietic stem cells; b) sequencing the sample to detect a degree of clonal hematopoiesis; c) comparing the degree of clonal hematopoiesis in the patient to a control degree; and d) determining the patient is at an elevated risk of the disease condition if the degree of clonal hematopoiesis in the patient is higher than the control degree in a statistically significant manner.

2. The method of claim 1 , wherein the degree of clonal hematopoiesis is measured using a variant allele frequency of mutations determined to be associated with clonal hematopoiesis.

3. The method of claim 2, wherein the variant allele frequency (VAF) is >2%.

4. The method of claim 3 wherein the VAF is > 5%.

5. The method of any one of claims 1-4, wherein the following genes are sequenced in the sample: TET2, DNMT3A, and ASXL1 , and optionally one or more of, but preferably all of, BOOR, BRAF, CALR, CBL, CEBPA, EZH2, FLT3A, GATA1 , GATA2, GNAS, IDH1 , IDH2, JAK2, KIT, KRAS, MPL, NRAS, PHF6, PPM1 D, PTPN11 , RAD21 , RUNX1 , SETBP1 , SF3B1 , SMC1A, SMC3, SRSF2, STAG2, TP53, U2AF1 , WT1, and ZRSR2.

6. The method of any one of claims 1-5, wherein the sequencing is performed using single-molecule molecular inversion probes (smMIPs).

7. The method of any one of claims 2-4, wherein the mutations associated with clonal hematopoiesis are detectable by the probes listed in Table A.

8. The method of any one of claims 2-4, wherein the mutations associated with clonal hematopoiesis are detected using a library comprising at least 50%, 60%, 70%, 80%, 90%, 95%, 98% or 99% of the probes listed in Table A.

9. The method of any one of claims 2-4, wherein the mutations associated with clonal hematopoiesis are detected using a library consisting of at least 50%, 60%, 70%, 80%, 90%, 95%, 98% or 99% of the probes listed in Table A.

10. The method of any one of claims 2-4, wherein the mutations associated with clonal hematopoiesis are detected using a library consisting of substantially all of the probes listed in Table A.

11. The method of any one of claims 2-4, wherein the mutations associated with clonal hematopoiesis are detected using a library consisting of the probes listed in Table A.

12. The method of any one of claims 1-11 , wherein the solid organ is a heart.

13. The method of claim 12, wherein the disease condition is cardiogenic shock.

14. The method of claim 13, wherein an elevated risk of cardiogenic shock is associated with an elevated risk of death.

15. The method of claim 13 or 14, further comprising treating or preventatively treating the patient for cardiogenic shock.

16. The method of claim 12, wherein the disease condition is an adverse outcome after orthotopic heart transplant (OHT).

17. The method of claim 16, wherein the adverse outcome is an elevated risk of mortality and/or elevated risk of cardiac allograft vasculopathy.

18. The method of claim 17, further comprising treating or preventatively treating the patient for cardiac allograft vasculopathy.

19. The method of claim 12, wherein the disease condition is hypertrophic cardiomyopathy.

20. The method of claim 19, further comprising treating or preventatively treating the patient for hypertrophic cardiomyopathy.

21. The method of any one of claims 1-11 , wherein the solid organ is a lung.

22. The method of claim 21 , wherein the disease condition is an adverse outcome, including death, after lung transplant.

23. The method of claim 22, further comprising treating or preventatively treating the patient for the adverse outcome after lung transplant.

24. A kit comprising a library of probes library comprising at least 50%, 60%, 70%, 80%, 90%, 95%, 98% or 99% of the probes listed in Table A.

25. The kit of claim 24, comprising a library consisting of at least 50%, 60%, 70%, 80%, 90%, 95%, 98% or 99% of the probes listed in Table A.

26. The kit of claim 24, comprising a library consisting of substantially all of the probes listed in Table A.

27. The method of any one of claims 2-4, comprising a library consisting of the probes listed in Table A.

28. A method of predicting the benefit of immunotherapy in a patient with melanoma, the method comprising: a) receiving a sample from the patient containing hematopoietic stem cells; b) sequencing the sample to detect a degree of clonal hematopoiesis in TET2; c) comparing the degree of TET2 clonal hematopoiesis in the patient to a control degree; and d) determining the patient would benefit from immunotherapy if the degree of TET2 clonal hematopoiesis in the patient is higher than the control degree in a statistically significant manner.

29. The method of claim 28, further comprising treating the patient with immunotherapy.

30. A method of predicting metastatic risk in a patient with a non-hematological cancer, the method comprising: a) receiving a sample from the patient containing hematopoietic stem cells; b) sequencing the sample to detect a degree of clonal hematopoiesis in TET2; c) comparing the degree of TET2 clonal hematopoiesis in the patient to a control degree; and d) determining the patient is at a lower risk of metastasis if the degree of TET2 clonal hematopoiesis in the patient is higher than the control degree in a statistically significant manner.

31 . The method of claim 30, further comprising treating the patient with a treatment and monitoring regimen reflective of a low risk of metastasis.